Tricylic indole compounds having affinity for serotonin receptor

ABSTRACT

Having an affinity against serotonine receptors, compound (I) shown below is useful as a therapeutic agent against various kinds of diseases of central nervous systems.  
                 
 
     (wherein R 1  is hydrogen; R 2  is hydrogen or lower alkyl; R 3  is hydrogen, —COOR 12  and so on; R 4  is hydrogen, lower alkyl and so on, or R 3  and R 4  taken together may form ═O or ═S; R 5  is hydrogen, or R 3  and R 5  taken together may form a bond; R 6  is hydrogen, —COOR 24  and so on; R 7  is hydrogen, halogen, lower alkyl and so on; R 8  is hydrogen, lower alkyl, cycloalkyl and so on; R 9 , R 10  and R 11  are each independently hydrogen, halogen, lower alkyl and so on)

TECHNICAL FIELD

[0001] The present invention is related to tricyclic indole compounds.Having an affinity against serotonin receptors, the present compoundsare useful as medicines, for example, a therapeutic agent for diseasesof central nervous system thereof and useful as synthetic intermediatesthereof.

BACKGROUND ART

[0002] Serotonin (5-hydroxytryptamine) is one of amines, which exists inliving body, and has a lot of physiological activities. For example,serotonin is located in granule cell of intestinal basal and promotesthe movement of the intestinal tract. And also, on an occasion ofbleeding, serotonin is released from platelets into blood and concernedwith hemostasis by contracting blood capillary. Apart from this,serotonin works as a neurotransmitter in brain and takes part inmodulating mental action, limit of pain, body-temperature andsleep-awakening cycle thereof, through serotonin receptors [Physiol.Rev. 72(1992) 165-229].

[0003] It has been reported that serotonin receptors are classifiedmainly to seven families and by including their subtypes, at least 14kinds of receptors have been identified until now. Each receptor isreported to be concerned with various kinds of physiological functionsand diseases [Pharmacol. Rev. 46(1994) 157-203]. Displaying to haveagonistic or antagonistic activities, an agent having a binding affinityagainst serotonin receptors, is expected to be a therapeutic orprophylactic medicament. [Pharmacol.Rev. 43(1991) 509-525].

[0004] Among them, 5-HT_(5A), 5-HT_(5B), 5-HT₆, and 5-HT₇ are receptorswhich have been recently identified and cloned [FEBS Lett. 355(1994)242-6, FEBS Lett. 333(1993) 25-31, J. Neurochem. 66(1996) 47-56, Neuron,11(1993) 449-458] and there is few report about the selective agonistand antagonist. Each of these receptors has already been known to belocated mainly in central nervous system. For example, it has beenreported that 5-HT_(5A) and 5-HT_(5B) receptors are located inhippocampus and cerebral cortex, which are profoundly concerned withlearning and memory [FEBS Lett. 355 (1994) 242-6, FEBS Lett. 333 (1993)25-31], 5-HT₆ receptor is located in corpus striatum, which is concernedwith motor function [J. Neurochem. 66 (1996) 47-56], and 5-HT₇ receptoris located in suprachiasmatic nucleus, which is concerned with mammalianbiological clock [Neuron, 11(1993) 449-458]. Therefore, there is apossibility for the selective agonist or antagonist against the receptorto be a therapeutic agent for dementia, Parkinson's disease, psychosisor diseases concerning circannual rhythm thereof. Selective agonists andantagonists against serotonin receptors other than 5-HT_(5A), 5-HT_(5B),5-HT₆ and 5-HT₇ receptors have already been launched as therapeuticagents for various kinds of diseases.

[0005] Furthermore, indole derivatives having an affinity againstserotonin receptors have been disclosed; for example, compounds of a4-membered ring type are disclosed in WO 96/32944, WO 95/28403, EP0738513 and so on and compounds of a 3-membered ring type are disclosedin GB 2341549, WO 98/00400, JP 99-189585A and so on. However, theseindole derivatives do not contain oxygen as an ring element. Moreover,naturally occurring heterocyclyl type of indole derivatives aredescribed in WO 00/59909.

[0006] Under the situations mentioned above, development of novelcompounds having an affinity against serotonin receptors and medicinescontaining them have been desired.

DISCLOSURE OF INVENTION

[0007] The present inventors have intensively studied to find thattricyclic indole compounds have an affinity against serotonin receptors,and accomplished the present invention shown below.

[0008] (1) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof of the formula:

[0009] wherein

[0010] R¹ is hydrogen;

[0011] R² is hydrogen or lower alkyl;

[0012] R³ is hydrogen, —COOR¹² (R¹² is hydrogen or ester residue) or—CN;

[0013] R⁴ is hydrogen, lower alkyl, —COOR¹³ (R¹³ is hydrogen or esterresidue), —CONR¹⁴R¹⁵ (R¹⁴ and R¹⁵ are each independently hydrogen, loweralkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl,optionally substituted aryl, or optionally substituted heteroaryl, orR¹⁴ and R¹⁵ taken together with a neighboring nitrogen atom may form 5-to 7-membered heterocycle), —CN, —NO₂, —NR¹⁶R¹⁷ (R¹⁶ and R¹⁷ are eachindependently hydrogen, —CN, optionally substituted lower alkyl,cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionallysubstituted aralkyl, optionally substituted aryl, optionally substitutedheteroaryl, or optionally substituted amino, or R¹⁶ and R¹⁷ takentogether with a neighboring nitrogen atom may form optionallysubstituted 5- to 7-membered heterocycle), —NR¹⁸COR¹⁹ (R¹⁸ and R¹⁹ areeach independently hydrogen, optionally substituted lower alkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, optionallysubstituted aralkyl, optionally substituted aryl, or optionallysubstituted heteroaryl), —NR²⁰COOR²¹ (R²⁰ is hydrogen, lower alkyl,cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionallysubstituted aralkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; R²¹ is ester residue), —NR²²SO₂R²³ (R²² ishydrogen, lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, loweralkenyl, optionally substituted aralkyl, optionally substituted aryl, oroptionally substituted heteroaryl; R²³ is lower alkyl, cycloalkyl, loweralkenyl, optionally substituted aralkyl, optionally substituted aryl,optionally substituted heteroaryl, or lower alkylamino), —OH, loweralkoxy, —SH, or lower alkylthio, or R³ and R⁴ taken together may form═O, ═S, or lower alkylenedioxy;

[0014] R⁵ is hydrogen, or R³ and R⁵ taken together may form a bond;

[0015] R⁶ is hydrogen, —COOR²⁴ (R²⁴ is hydrogen or ester residue), —CN,or —CH₂NR²⁵R²⁶ (R²⁵ and R²⁶ are each independently hydrogen, loweralkyl, cycloalkyl, or lower alkenyl);

[0016] R⁷ is hydrogen, halogen, —CN, optionally substituted lower alkyl,cycloalkyl, cycloalkyl(lower)alkyl, optionally substituted loweralkenyl, optionally substituted aralkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted amino, —COOR³⁴(R³⁴ is hydrogen or ester residue), —COR³⁵ (R³⁵ is hydrogen, loweralkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl,optionally substituted amino, optionally substituted aryl, or optionallysubstituted heteroaryl) or —CHNOH;

[0017] R⁸ is hydrogen, optionally substituted lower alkyl, cycloalkyl,cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl,optionally substituted aryl, optionally substituted heteroaryl, —COR²⁷(R²⁷ is hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionallysubstituted aralkyl, optionally substituted aryl, or optionallysubstituted heteroaryl, —COOR²⁸ (R²⁸ is ester residue), —SO₂R²⁹ (R²⁹ islower alkyl, cycloalkyl, optionally substituted lower alkenyl,optionally substituted aralkyl, optionally substituted aryl, optionallysubstituted heteroaryl) or tri-lower alkylsilyl;

[0018] R⁹, R¹⁰ and R¹¹ are each independently hydrogen, halogen,optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl,optionally substituted lower alkenyl, lower alkoxy, —OH, —CN, —SR³⁰ (R³⁰is hydrogen or lower alkyl), —CONH₂, —CHO, —CHNOH, —COOR³¹ (R³¹ ishydrogen or ester residue), —NR³²R³³ (R³² and R³³ are each independentlyhydrogen or lower alkyl), optionally substituted aryl, or optionallysubstituted heteroaryl.

[0019] (2) A compound, prodrug, pharmaceutically acceptable salt, orsolvate thereof according to the above 1, wherein R² is hydrogen.

[0020] (3) A compound, prodrug, pharmaceutically acceptable salt, orsolvate thereof according to the above 1, wherein R³ is hydrogen.

[0021] (4) A compound, prodrug, pharmaceutically acceptable salt, orsolvate thereof according to the above 1, wherein R⁵ is hydrogen.

[0022] (5) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R³ and R⁵ takentogether may form a bond.

[0023] (6) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R³ and R⁴ takentogether may form ═O, ═S or lower alkylenedioxy.

[0024] (7) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R⁴ represents —COOR¹³(R¹³ is hydrogen or lower alkyl), —NR¹⁶R¹⁷ (R¹⁶ and R¹⁷ are eachindependently hydrogen, optionally substituted lower alkyl, cycloalkyl,lower alkenyl, optionally substituted aralkyl, optionally substitutedamino, or R¹⁶ and R¹⁷ taken together may form an optionally substituted5 to 7 membered heterocyclyl ring with the neighboring nitrogen atom),—NR¹⁸COR¹⁹ (R¹⁸ and R¹⁹ are each independently hydrogen, optionallysubstituted lower alkyl or optionally substituted aralkyl), —NR²⁰COOR²¹(R²⁰ is hydrogen, or lower alkyl; R²¹ is an ester moiety), —NR²²SO₂R²³(R²² is hydrogen; R²³ is lower alkyl or lower alkylamino), —OH, or loweralkoxy.

[0025] (8) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R⁴ is —COOR¹³ (R¹³ ishydrogen or methyl), —NR¹⁶R¹⁷ (R¹⁶ is hydrogen or lower alkyl, R¹⁷ ishydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkenyl,optionally substituted aralkyl, optionally substituted amino, optionallysubstituted amino or R¹⁶ and R¹⁷ are taken together may form anoptionally substituted 5 to 7 membered heterocyclyl ring with theneighboring nitrogen atom), —NR¹⁸COR¹⁹ (R¹⁸ is hydrogen, R¹⁹ ishydrogen, optionally substituted lower alkyl or optionally substitutedaralkyl), —NR²⁰COOR²¹ (R²⁰ is hydrogen or methyl; R²¹ is methyl),—NR²²SO₂R²³ (R²² is hydrogen; R²³ is methyl or methylamino), —OH, orlower alkoxy.

[0026] (9) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R⁴ is —NH₂, —NHCH₃ or—N(CH₃)₂.

[0027] (10) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R⁶ is hydrogen,COOCH₃, COOCH₂CH₃, CN, or CH₂NH₂.

[0028] (11) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R⁶ is hydrogen.

[0029] (12) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R⁷ is hydrogen, loweralkyl, halogen, phenyl, —COOR³⁴ (R³⁴ is mentioned before), —CHO or—CHNOH.

[0030] (13) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R⁷ is hydrogen,methyl, ethyl, halogen or phenyl.

[0031] (14) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R⁸ is hydrogen,optionally substituted lower alkyl, —COR²⁷ (R²⁷ is hydrogen, loweralkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl,optionally substituted aryl, or optionally substituted heteroaryl),—COOR²⁸ (R²⁸ is ester moiety), or —SO₂R²⁹ (R²⁹ is lower alkyl,cycloalkyl, optionally substituted lower alkenyl, optionally substitutedaralkyl, optionally substituted aryl, optionally substitutedheteroaryl), or tri-lower alkylsilyl.

[0032] (15) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R⁸ is hydrogen or—SO₂R²⁹ (R²⁰ is mentioned before)

[0033] (16) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein all of R⁹, R¹⁰ andR¹¹ are hydrogen.

[0034] (17) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R² is hydrogen; R³and R⁵ are both hydrogen or taken together may form a bond.

[0035] (18) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 16 and 17, wherein R⁶ ishydrogen, COOCH₃, COOCH₂CH₃, CN, or CH₂NH₂; R⁷ is hydrogen, lower alkyl,halogen or phenyl; R⁸ is hydrogen, lower alkyl, COPh, or SO₂Ph (Phrepresents phenyl).

[0036] (19) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R⁹ is hydrogen orhalogen.

[0037] (20) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R⁹ is hydrogen.

[0038] (21) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R¹⁰ is hydrogen.

[0039] (22) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R¹¹ is hydrogen,halogen, lower alkyl, optionally substituted lower alkenyl, —CN, —SR³⁰(R³⁰ is hydrogen or lower alkyl), —CONH₂, —CHO, —CHNOH, —NR³²R³³ (R³²and R³³ are each independently hydrogen or lower alkyl) or aryl.

[0040] (23) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R¹¹ is hydrogen,halogen, methyl, —CN, or —CONH₂.

[0041] (24) A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to the above 1, wherein R¹, R², R³, R⁵, R⁶,R⁹, and R¹⁰ is hydrogen; R⁴ is —NH₂, —NHCH₃, or —N(CH₃)₂; R⁷ ishydrogen, halogen, lower alkyl, or phenyl; R⁸ is hydrogen or —SO₂R²⁹(R²⁹ is mentioned before); R¹¹ is hydrogen, halogen, lower alkyl, —CN,or —CONH₂.

[0042] (25) A pharmaceutical composition containing a compound, prodrug,pharmaceutically acceptable salt or solvate thereof according to any oneof the above 1-24.

[0043] (26) A therapeutic or prophylactic medicament against theserotonin receptors mediated diseases, comprising a compound, prodrug,pharmaceutically acceptable salt or solvate thereof according to any oneof the above 1-24.

[0044] (27) A therapeutic or prophylactic medicament according to theabove 26, wherein the serotonine receptor is a 5-HT₆ receptor.

[0045] (28) A therapeutic or prophylactic medicament according to theabove 26, wherein the disease is that of central nervous system.

[0046] (29) A therapeutic or prophylactic medicament according to theabove 28, wherein the disease of the central nervous system isschizophrenia, Alzheimer's disease, Parkinson's disease, depression,anxiety, pain or migraine.

[0047] (30) A method for treating or preventing the serotonin receptorsmediated diseases, which comprises administrating to said mammal aneffective amount of a compound, prodrug, pharmaceutically acceptablesalt or solvate thereof according to any one of the above 1-24.

[0048] (31) Use of a compound, prodrug, pharmaceutically acceptable saltor solvate thereof according to any one of the above 1-24, in order toprepare a therapeutic or prophylactic medicament for the serotoninreceptors mediated diseases.

BEST MODE FOR CARRYING OUT THE INVENTION

[0049] Each group of compound (I) is explained below. Each term usedherein is defined to have meanings described below in either case of asingle or a joint use with other terms, unless otherwise noted.

[0050] “Halogen” refers to F, Cl, Br, I.

[0051] “Lower alkyl” includes a straight-chain and branched-chain C₁-C₆alkyl group and refers to methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl,tert-pentyl, n-hexyl and the like, preferably a C₁-C₄ alkyl group andmore preferably a C₁-C₃ alkyl group, such as methyl, ethyl, n-propyl,and i-propyl.

[0052] “Lower alkenyl” includes a straight-chain and branched-chainC₂-C₆ alkenyl group and refers to vinyl, allyl, 1-propenyl, 2-butenyl,3-butenyl, 1-pentenyl, prenyl, 2-hexenyl and the like, preferably vinyl,allyl or prenyl and the like.

[0053] “Lower alkoxy” includes oxy groups binding to an above mentionedlower alkyl group, and refers to methoxyl, ethoxyl, n-propoxyl,i-propoxyl, tert-butoxy, pentyloxy, hexyloxy and the like, preferably aC₁-C₄ alkoxyl group and more preferably a C₁-C₃ alkoxyl group such asmethoxyl, ethoxyl, n-propoxyl, and i-propoxyl.

[0054] “Cycloalkyl” includes C₃-C₈ cycloalkyl and refers to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and thelike, preferably a C₅-C₇ cycloalkyl group such as cyclopentyl,cyclohexyl, and cycloheptyl.

[0055] “Cycloalkyl(lower)alkyl” means an above mentioned lower alkylgroup bound with an above mentioned cycloalkyl group and refers tocyclopropylmethyl, 2-cyclopropyl ethyl and the like.

[0056] “Lower alkylthio” includes a thio group bound with an abovementioned lower alkyl group and refers to methylthio, ethylthio,i-propylthio, tert-butylthio, pentylthio, hexylthio and the like,preferably methylthio.

[0057] “Aryl” used herein means a single or fused aromatic hydrocarbonring system and refers to phenyl, naphthyl (such as α-naphthyl, andβ-naphthyl), anthryl, indenyl, phenanthryl and the like, preferablyphenyl or naphthyl.

[0058] “Lower alkylenedioxy” includes a straight-chain andbranched-chain C₁-C₆ alkylendioxy group, preferably methylenedioxy,ethylenedioxy, or trimethylenedioxy, more preferably ethylenedioxy.

[0059] “Aralkyl” used herein means a lower alkyl group bound with anabove mentioned aryl group, refers to benzyl, phenethyl, phenylpropyl(such as 3-phenylpropyl), naphthylmethyl (such as α-naphthylmethyl),anthrylmethyl such as 9-anthrylmethyl and the like.

[0060] “Heteroaryl” used herein means a single or polycyclic aromaticring system in which the ring contains the same or different heteroatomselected from the group of O, S and N.

[0061] The single aromatric ring system includes a 5- to 7-membered ringmoiety in which the heterocycle contains 1 to 4 heteroatoms and refersto furyl, thienyl, tetrazolyl, pyrrolyl, pyrazolyl, imidazolyl,oxazolyl, thiazolyl, thiadiazolyl, pyridinyl, oxazinyl, triazinyl andthe like, preferably 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl,3-pyrrolyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl.

[0062] Polycyclic aromatic ring system includes a di- ortri-heterocyclic moiety in which the heterocycle contains 1 to 5heteroatoms and refers to benzofuranyl, isobenzofuranyl, benzothienyl,indolyl, isoindolyl, indazolyl, benzimidazolyl, benzoxazoly,benzothiazolyl, benzotriazolyl and the like.

[0063] 5- to 7-Membered heterocycle formed by “R¹⁴ and R¹⁵” or “R¹⁶ andR¹⁷” taken together with the neighboring nitrogen, refers topyrrolydine, piperidine, azepine, piperazine, morpholine and the like,preferably pyrrolydine, piperazine or morpholine.

[0064] Substituents on the aryl, heteroaryl or heterocyclyl ring referto halogen, hydroxy, amino, carboxy, cyano, nitro, carbamoyl, sulfamoyl,lower alkyl (such as methyl or ethyl), halo-lower alkyl (such as —CCF₃),lower alkyl-carbamoyl (such as methylcarbamoyl), lower alkyl-sulfamoyl(such as methylsulfamoyl), lower alkoxy (such as methoxyl), loweralkoxycarbonyl (such as ethoxylcarbonyl), a 5- to 7-memberedheterocyclyl group such as isoxazolyl and the like, preferably halogen,methyl, methoxyl, trihalo-methyl such as trifluoromethyl. preferably 1to 3 of these groups can be substituted.

[0065] “Ester” residue refers to lower alkyl, optionally substitutedaralkyl and the like, preferably, methyl, ethyl, n-propyl, i-propyl,tert-butyl, benzyl and the like.

[0066] “Lower alkyl” or “lower alkenyl” can be optionally substituted,in which a substituent refers to hydroxy, halogen, amino and optionallymono- or di-lower alkyl substituted carbamoyl (such as carbamoyl, anddimethylcarbamoyl), phenyl, phenylamino, cyclohexylamino, lower alkoxy,lower alkoxycarbonyl such as methoxylcarbonyl and the like.

[0067] An optional substitutent on amino groups refers to lower alkyl,lower alkoxycarbonyl and the like.

[0068] Preferred examples are shown below.

[0069] (1) both of R¹ and R⁵ are hydrogen.

[0070] (2) all of R¹, R³, and R⁵ are hydrogen.

[0071] (3) R¹ is hydrogen; R³ and R⁴ are taken together may form a bond.

[0072] (4) R¹ is hydrogen; R³ and R⁴ are taken together may form ═O or═S.

[0073] Other preferred examples are shown in following tables. TABLE 1R² R³ R⁴ R⁶ H H H H methyl COOR¹² methyl COOR²⁴ ethyl CN ethyl CNn-propyl n-propyl CH₂NR²⁵R²⁶ i-propyl i-propyl COOR¹³ CONR¹⁴R¹⁵ CN NO₂NR¹⁶R¹⁷ NR¹⁸COR¹⁹ NR²⁰COOR²¹ NR²²SO₂R²³ OH methoxyl ethoxyl n-propoxyli-propoxyl SH methyl thio ethyl thio n-propylthio i-propylthio—O(CH₂)₂O—

[0074] TABLE 2 R⁷ R⁸ R⁹, R¹⁰, R¹¹ H H H F methyl F Cl ethyl Cl Brn-propyl Br I i-propyl I methyl cyclopropylmethyl methyl ethylcyclopentyl ethyl n-propyl cyclohexyl n-propyl i-propyl cycloheptyli-propyl cyclopropylmethyl vinyl cyclopropylmethyl cyclopentyl allylcyclopentyl cyclohexyl prenyl cyclohexyl cycloheptyl benzyl cycloheptylvinyl phenethyl vinyl allyl phenyl allyl prenyl 2-furyl prenyl benzyl3-furyl OH phenethyl 2-pyridinyl methoxyl phenyl 3-pyridinyl ethoxyl2-furyl 4-pyridinyl n-propoxyl 3-furyl 2-pyrrolyl i-propoxyl 2-pyridinyl3-pyrrolyl CN 3-pyridinyl 2-thienyl CHO 4-pridinyl 3-thienyl SCH₃2-pyrrolyl COR²⁷ CH═N—OH 3-pyrrolyl COOR²⁸ CONH₂ 2-thienyl SO₂R²⁹ phenyl3-thienyl Si(iPr)₃ CH═CHCO₂CH₃ CN

[0075] TABLE 3 R¹², R¹³ R¹⁴, R¹⁶ R¹⁵, R¹⁷ H H H methyl methyl methylethyl ethyl ethyl n-propyl n-propyl n-propyl i-propyl i-propyl i-propylt-butyl cyclopropyl methyl cyclopropylmethyl benzyl cyclopentylcyclopentyl cyclohexyl cyclohexyl cycloheptyl cycloheptyl allyl allylprenyl prenyl benzyl benzyl phenethyl phenethyl phenyl phenyl 2-furyl2-furyl 3-furyl 3-furyl 2-pyridinyl 2-pyridinyl 3-pyridinyl 3-pyridinyl4-pyridinyl 4-pyridinyl 2-pyrrolyl 2-pyrrolyl 3-pyrrolyl 3-pyrrolyl2-thienyl 2-thienyl 3-thienyl NHBoc cyclopropyl CH₂CF₃ —CH₂CH₂CH₂CH₂——CH₂CH₂CH₂CH₂CH₂— —CH₂CH₂CH₂CH₂CH₂CH₂— —CH═CH—CH═CH— —CH₂CH₂NHCH₂CH₂——CH₂CH₂NCH₃CH₂CH₂— —CH₂CH₂OCH₂CH₂—

[0076] TABLE 4 R²¹ R¹⁸, R¹⁹, R²⁰, R²² R²³ methyl H methyl ethyl methylethyl n-propyl ethyl n-propyl i-propyl n-propyl i-propyl t-butyli-propyl cyclopropylmethyl benzyl cyclopropylmethyl cyclopentylcyclopentyl cyclohexyl cyclohexyl cycloheptyl cycloheptyl vinyl allylallyl prenyl prenyl benzyl benzyl phenethyl phenethyl phenyl phenyl2-furyl 2-furyl 3-furyl 3-furyl 2-pyridinyl 2-pyridinyl 3-pyridinyl3-pyridinyl 4-pyridinyl 4-pyridinyl 2-pyrrolyl 2-pyrrolyl 3-pyrrolyl3-pyrrolyl 2-thienyl 2-thienyl 3-thienyl 3-thienyl CH₂N(CH₃)₂ NHCH₃ CF₃CH₂NH-cyclohexyl

[0077] TABLE 5 R²⁴ R²⁵, R²⁶ H H methyl methyl ethyl ethyl n-propyln-propyl i-propyl i-propyl t-butyl cyclopropylethyl benzyl cyclopentylcyclohexyl cycloheptyl vinyl allyl prenyl

[0078] TABLE 6 R²⁷ R²⁸ R²⁹ H methyl methyl methyl ethyl ethyl ethyln-propyl n-propyl n-propyl i-propyl i-propyl i-propyl t-butylcyclopropylmethyl cyclopropylmethyl benzyl cyclopentyl cyclopentylcyclohexyl cyclohexyl cycloheptyl cycloheptyl vinyl vinyl allyl allylprenyl prenyl benzyl benzyl phenethyl phenethyl phenyl phenyl 2-furyl2-furyl 3-furyl 3-furyl 2-pyridinyl 2-pyridinyl 3-pyridinyl 3-pyridinyl4-pyridinyl 4-pyridinyl 2-pyrrolyl 2-pyrrolyl 3-pyrrolyl 3-pyrrolyl2-thienyl 2-thienyl 3-thienyl 3-thienyl α-naphthyl mono or diCl-phenylCF₃-phenyl Br-phenyl mono or dimethoxy phenyl Br-di F-phenyl phenylvinyl mono or diF-phenyl Cl-thienyl isoxyazolylthienyl

[0079] The following cases are more preferable.

[0080] R² is more preferably hydrogen or methyl and particularlypreferable is hydrogen.

[0081] R³ and R⁵ are more preferably both hydrogen or taken together mayform a bond and particularly preferable is hydrogen.

[0082] R⁴ is preferably —COOR¹³ (R¹³ is hydrogen or lower alkyl),—NR¹⁶R¹⁷ (R¹⁶ and R¹⁷ is each independently hydrogen, optionallysubstituted lower alkyl, cycloalkyl, lower alkenyl, optionallysubstituted aralkyl, optionally substituted amino, or R¹⁶ and R¹⁷ takentogether may form optionally substituted 5- to 7-membered heterocyclylwith the neighboring nitrogen atom), —NR¹⁸COR¹⁹ (R¹⁸ and R¹⁹ are eachindependently hydrogen, optionally substituted lower alkyl or optionallysubstituted aralkyl), —NR²⁰COOR²¹ (R²⁰ is hydrogen, or lower alkyl; R²¹is ester residue), —NR²²SO₂R²³ (R²² is hydrogen; R²³ is lower alkyl orlower alkylamino), —OH, lower alkoxy. R⁴ is preferably —COOR¹³ (R¹³ ishydrogen or methyl), —NR¹⁶R¹⁷ (R¹⁶ is hydrogen or lower alkyl, R¹⁷ ishydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkenyl,optionally substituted aralkyl, optionally substituted amino, or R¹⁶ andR¹⁷ taken together may form optionally substituted 5- to 7-memberedheterocyclyl with the neighboring nitrogen atom), —NR¹⁸COR¹⁹ (R¹⁸ ishydrogen, R¹⁹ is hydrogen, optionally substituted lower alkyl oroptionally substituted aralkyl), —NR²⁰COOR²¹ (R²⁰ is hydrogen or methyl;R²¹ is methyl), —NR²²SO₂R²³ (R²² is hydrogen; R²³ is methyl ormethylamino), —OH, lower alkoxy. R⁴ is preferably —NH₂, —NHCH₃, or—N(CH₃)₂.

[0083] R⁶ is more preferably hydrogen, COOMe (Me is methyl), COOEt (Etis ethyl), CN, or CH₂NH₂, more preferably hydrogen.

[0084] R⁷ is preferably hydrogen, lower alkyl, halogen, phenyl, —COOR³⁴(R³⁴ is hydrogen or ester residue), —CHO or —CHNOH, more preferablyhydrogen, methyl, ethyl, halogen, or phenyl.

[0085] R⁸ is more preferably hydrogen, optionally substituted loweralkyl, —COR²⁷ (R²⁷ is hydrogen, lower alkyl, cycloalkyl, lower alkenyl,optionally substituted aralkyl, optionally substituted aryl, oroptionally substituted heteroaryl), —COOR²⁸ (R²⁸ is ester residue), or—SO₂R²⁹ (R²⁹ is lower alkyl, cycloalkyl, optionally substituted loweralkenyl, optionally substituted aralkyl, optionally substituted aryl,optionally substituted heteroaryl), or tri-lower alkyl silyl, morepreferably hydrogen or —SO₂R²⁹ (R²⁹ is lower alkyl, cycloalkyl,optionally substituted lower alkenyl, optionally substituted aralkyl,optionally substituted aryl, optionally substituted heteroaryl). R²⁹ ismore preferably mono- or di-Cl-phenyl, CF₃-phenyl, Br-phenyl, mono- ordi-methoxyphenyl, phenylvinyl, mono- or di-F-phenyl, Cl-thienyl,naphthyl.

[0086] R⁹ is preferably hydrogen or halogen, more preferably hydrogen.

[0087] R¹⁰ is preferably hydrogen.

[0088] R¹¹ is preferably hydrogen, halogen, lower alkyl, optionallysubstituted lower alkenyl, —CN, —SR³⁰ (R³⁰ is hydrogen or lower alkyl),—CONH₂, —CHO, —CHNOH, —NR³²R³³ (R³² and R³³ is each independentlyhydrogen or lower alkyl) or aryl, more preferably hydrogen, halogen,methyl, —CN, or —CONH₂.

[0089] In a preferred compound among compound (I), R¹, R², R³, R⁵, R⁶,R⁹, and R¹⁰ are hydrogen; R⁴ is —NH₂, —NHCH₃, or —N(CH₃)₂; R⁷ ishydrogen, halogen, lower alkyl or phenyl; R⁸ is hydrogen or —SO₂R²⁹ (R²⁹is mentioned before); R¹¹ is hydrogen, halogen, lower alkyl, —CN, or—CONH₂.

[0090] A produg of compound (I) is a derivative of compound (I), whichhas a chemically or metabolically decomposible group and can get back toa pharmaceutically active present invention compound by the solvolysisor under physiological conditions in vivo. Methods of selection andproduction of a suitable prodrug derivative has been disclosed, forexample in Design of Prodrugs, Elsevier, Amsterdam 1985. Having acarboxylic acid group, the original acidic compound can be exemplifiedto be reacted with an appropriate alcohol derivative to give the esterderivative or reacted with a suitable amino derivative to give the amidederivative as the prodrug. Having a hydroxyl group, the hydroxylcompound for example can be exemplified to be reacted with appropriateacid halides or acid anhydrides to give the acyloxy derivative as theprodrug. Having an amino group, the amino compound can be exemplified tobe reacted with a suitable acid halide or acid anhydride to give theamide compound as the prodrug.

[0091] A pharmaceutically acceptable salt of compound (I) or the prodrugrefers to those salts, which are obtained by reacting with inorganicacids, inorganic bases, ammonia, organic bases, inorganic acids, organicacids, basic amino acids, ionic halogen and the like, or the internalsalt. The inorganic base refers to alkaline metals (Na, K and the like),alkaline-earth metal (Ca, Mg and the like). Organic base refers totrimethylamine, triethylamine, corrine, procaine, ethanolamine and thelike. The inorganic acid refers to hydrochloric acid, hydrogen bromide,sulfuric acid, nitric acid, phosphoric acid, and the like. The organicacid refers to p-toluenesulfonic acid, methanesulfonic acid, formicacid, trifluoroacetic acid, maleic acid and the like. Basic amino acidrefers to lysine, arginine, ornithine, histidine and the like.

[0092] A solvate of compound (I) refers to the hydrate or alcholate andthe like. The racemic or the optically active compound (I) and the likeare all included in the present invention.

[0093] Compound (I) can be prepared from indole derivatives and the likeas starting material which are well known or can be obtained easily bythe synthesis. General method of preparation is shown below.

[0094] (The 1st Process)

[0095] Compound (III) can be obtained by reacting indole derivative (II)with vinyl compound (IV) (X¹ is H) in the presence of a base. Thisreaction can be accomplished fundamentally according to theBaylis-Hillman vinyl alkylation condition. The reaction temperature canbe exemplified to be −20-50° C. and the solvent can be illustrated to betetrahydrofuran (THF), dioxane, dichloromethane, chloroform and thelike. Excess vinyl compound can be used as the solvent, also. As thebase, 1,4-diazabicyclo[2,2,2]octane (DABCO), tri-n-butylphosphine andthe like can be exemplified. The reaction time is ordinarily severalhours to several days.

[0096] The preparation of compound (III) is also possible by reactingthe acetylene compound R²C≡CR⁴ (V) with the vinyl compound (III) (X¹ isAl(i-Bu)₂), obtained from compound R²C≡CR⁴ (V) anddiisopropylaluminumhydride (DIBAL). The reaction to the vinyl aluminumcompound can be carried out according to a similar manner of well-knownmethods (for example: the method is disclosed in J. Org. Chem., 1988,53, 1037.). The reaction temperature is exemplified to be ordinarily−100 to 50° C. and the solvent is tetrahydrofuran (THF), dioxane,dichloromethane and the like. The reaction temperature is normallyseveral hours to tens of hours.

[0097] (The 2nd Process)

[0098] Compound (III) is cyclized under a Mitsunobu reaction conditionto give compound (I-1) of the present invention. The Mitsunobu reactioncan be carried out according to the well-known ordinary method (forexample, a method disclosed in Synthesis, 1981,1.). The reactiontemperature used are exemplified to be −50-50° C. and the solvent usedare exemplified to be tetrahydrofuran (THF), dioxane, benzene, toluene,dichloromethane and the like, respectively. Among reagents,1,1′-(azodicarbonyl )-diethyl ester, 1,1′-(azodicarbonyl)-diisopropylester, 1,1′-(azodicarbonyl)-dipiperidine and the like are used in thisreaction as diazocarboxylic acid ester derivatives. Further,triphenylphosphine, tri-n-butylphosphine and the like can be exemplifiedas phosphine derivatives. The reaction time is ordinarily several hoursto tens of hours.

[0099] Furthermore, compound (I-1) can be obtained by cyclizing compound(III) in the presence of base. Moreover, in order to increase the yieldof the reaction, it is preferable that the secondary hydrokyl group isfirst changed to the appropriate removable group such as acetoxyl groupand the like and then the cyclization reaction is carried out in thepresence of base. The reaction temperature can be exemplified to be0-100° C. and the solvents can be exemplified to be tetrahydrofuran(THF), dioxane, toluene, acetone, acetonitrile, and the like,respectively. Potassium carbonate, NaH, pyridine, triethylamine and thelike can be exemplified as the base used. The reaction time isordinarily several hours to tens of hours.

[0100] Furthermore, it is possible in the 1st process to convert tocompound (I-1) through the only one step by reacting compound (II) withcompound (IV) (X¹ is H) at relatively high temperature (20-50° C.).

[0101] Furthermore, it is possible to convert to compound (I-1) throughthe only one step by reacting compound (II) and compound (IV) (X¹ is—PO(OMe)₂) under the presence of base. The reaction temperature isordinarily −20-50° C. Tetrahydrofuran (THF), dioxane, toluene,dichloromethane and the like can be exemplified as the solvent.Potassium tert-butoxyde and the like can be exemplified as the base. Thereaction time is ordinarily several hour to tens of hours.

[0102] According to the above reaction, preferably a compound, in whichR⁴ in compound (I-1) is electron-withdrawing group, is obtained. As theelectron-withdrawing group, ester group, carboxylic acid group, cyanogroup, amide group, aldehyde group, nitro group and the like areexemplified.

[0103] Compound (I-1) is a compound (I) in the present invention, whereR¹ and R⁶ are both hydrogen and R³ and R⁵ taken together may form abond. Compound (I-1) can be derived to other compounds of the presentinvention by chemical modifications. For example, compound (I-1), whereR⁴ is carboxylic acid, can be transferred to the various kinds of esterand amide compounds by converting to the acid chloride with thionylchloride and the like or to the acid anhydride with ethyl chloroacetateand the like under the existence of base such as triethylamine, followedby reacting with the various kinds of alcohol or amino derivatives.Furthermore, compound (I-1) can also be transferred to the various kindsof ester and amide compounds by using appropriate condensing agents suchas dicyclohexylxarbodiimide, carbonyldiimidazole and the like. Further,if the reaction is carried out according to Curtius reaction or Hofmannreaction, compound in which R⁴ is carbamate can be obtained. Moreover,compound in which R⁴ is hydroxy (or R³ and R⁴ taken together may form═O) can be prepared by the hydrolysis of the compound in which R⁴ iscarbamate. Furthermore, by reduction catalytically or with sodiumborotriacetoxyhydride under the presence of appropriate base, compound,in which R³ and R⁴ taken together may form ═O, can be transferred tocompounds in which R⁴ is various kind of N-alkyl groups.

[0104] (The 3rd Process))

[0105] Compound (I-2) of the present invention can be obtained by thereduction of compound (I-1). Compound (I-2) is a compound (I) of thepresent invention, where all of R¹, R³, R⁵ and R⁶ are hydrogen. Thereduction reaction is carried out preferably by a catalytic reduction(Pd/C, H₂) thereof. By further chemical modifications of compound (I-2),another compound of the present invention can be obtained. For example,in the case where R⁴ is primary or secondary amino group, compound (I-2)can be converted to the various kinds of N-sulfonyl or N-acyl compoundsby reacting with various kinds of sulfonyl chloride or acyl chloride inthe presence of base such as triethylamine and the like. Furthermore,compound (I-2) can be transferred to various kinds of N-alkyl compoundsby reacting with various kinds of alkyl halide under the presence ofbase such as triethylamine and the like or by reduction catalytically orwith sodium triacetoxyborohydride in the presence of various kinds ofaldehydes or ketones.

[0106] Compound (I-3) of the present invention can be obtained bycyclization of indole derivative (IV) (X² is a removing group such aslower alkoxy and the like) preferably under the presence of base.Compound (I-3) is a compound in which R³ and R⁵ taken together may forma bond and R⁴ is a hydroxy group in compound (I). As the solvent, ether,tetrahydrofuran (THF), dioxane and the like are exemplified. NaH, sodiummetal, potassium tert-butoxyde lithium bis(trimethylsilyl)amide and thelike are exemplified as the base. The reaction time is ordinarilyseveral hours to tens hours. By this reaction, a preferred compound isobtained, in which R⁶ is an electron-withdrawing group such ascarboxylic acid group, ester group, cyano group.

[0107] Moreover, R¹ and R² are preferably hydrogen in the abovepreparations. Furthermore, if necessary, the group can be protectedbefore the reaction and de-protected after the reaction by thewell-known method. For example, R⁸ in the intermediate is preferably anamino protecting group such as Boc. Compounds obtained by the abovemethod of preparation of the present invention can be transferred toanother compound of this invention by further chemical modifications ofwell-known reaction such as oxidation, reduction, protection,deprotection, rearrangement reaction, halogenation, hydroxylation,alkylation, alkylthiolation, demethylation, O-alkylation, O-acylation,N-alkylation, N-alkenylation, N-acylation, N-cyanation, N-sulfonylation,coupling reaction using transition metals and the like.

[0108] Having an affinity against various kinds of serotonin receptors,compound (I) has functions as the agonist or antagonist. Therefore,compound (I) is useful as a therapeutic or prophylactic medicine tovarious serotonin receptor mediated diseases, such as diseases ofcentral nervous systems such as sleep-awakening lesion, circadian rhythmlesion, anxiously mental disorder, schizophrenia, cerebral stroke,dementia, pain, Alzheimer's disease, Parkinson's disease, depression,anxiety, megrim and the like. A specifically preferable compound (I)described above has an affinity against 5HT_(1A), 5HT₆, 5HT₇ amongserotonin receptors and more preferably has a high selective affinityagainst 5HT₆. Increase of the selectivity against 5HT₆ can be achievedpreferably by introducing various kinds of substituents to R⁷ and R¹¹and so on. Then, compound (I) is useful to the selectively 5HT₆ receptormediated diseases among the diseases of central nervous system (forexample, schizophrenia, Alzheimer's disease, Parkinson's disease,depression, anxiety, migraine and the like).

[0109] Compound (I) can be administrated orally or parenterally tomammals including human. Granule, tabula, capsules, injections,suppositorium and the like can be exemplified as an admirable dosageform. In pharmaceutical manufacturing, if necessary, following variousadditive agents can be used, for example remedium constituens (lactose,mannitol, crystalline cellulose, starch and the like), disintegrators(carmellose, hydroxypropylmethyl cellulose, polyvinylpolypyrrolidone andthe like), binding agent (methylcellose, hydroxypropylcellose, cellose,poloyvinylalcohol and the like), lubricant (Magnesium stearate, talc andthe like), stabilizing agent, coloring agent, coating material. Dosagevaries depending on the examinee's age, body weight, condition ofdiseases and dosage forms and so on. Generally, dosage is ca. 0.001 mgto 1 g/day to an adult in oral or parenteral administration. Number ofadministration time is one to several times/day.

[0110] Examples of this invention are described below without limitingthe present invention thereto. “Ex” in the Scheme of reactioncorresponds to the number of Example, e.g. “Ex 1” means compound (1)obtained by the procedure cited in Example 1.

[0111] (Abbreviated Words)

[0112] Me=methyl; Et=ethyl; tBu=t-butyl; nPr=n-propyl; Ph=phenyl;Ts=p-toluene sulfonyl; Bn=benzyl; Ms=methanesulfonyl

EXAMPLE 1 OF REFERENCE

[0113]

4-Hydroxyindole-3-carbaldehyde (1-1) (R⁷═R¹¹═H)

[0114] Phosphorous oxychloride 7.35 ml was added dropwise to drydimethylformamide 15 ml under cooling in ice-methanol bath and themixture was stirred for 15 min. Then, a solution of the 4-hydroxyindole5.0 g in dry dimethylformamide 10 ml was added dropwise to the mixtureunder cooling in ice and the mixture was stirred for 2 h at roomtemperature. Water was added under cooling in ice to the mixture, whichwas made alkaline with a 30% aqueous sodium hydroxide solution and wasstirred for 15 min. Then, the mixture was acidified to pH 4 with 5N-HCland the precipitate was collected by filtration, washed with water anddried to give the titled compound 4.99 g as crude crystalline materials.Yield 82%. Crude crystalline materials are recrystallized from methanolto give yellow crystals m.p. 190-193° C.

[0115]¹H-NMR(DMSO-d₆): 6.54 (1H, dd, J=8.1, 0.9 Hz), 6.95 (1H, dd,J=8.1, 0.9 Hz), 7.13 (1H, t, J=8.1 Hz), 8.37 (1H, s), 9.64 (1H, s),10.54 (1H, br s), 12.35 (1H, br s).

[0116] Following compounds were obtained, according to the similartreatment. Comp m.p. No R⁷ R¹¹ (° C.) ¹H-NMR (DMSO-d₆) 1-2 Ph H 239-2476.57 (1H, dd, J=8.1, 0.9 Hz), 6.95 (dec.) (1H, dd, J=8.1, 0.9 Hz), 7.17(1H, t, J=8.1 Hz), 7.61-7.82 (5H, m), 9.56 (1H, s), 11.05 (1H, s), 12.67(1H, br s) 1-3 Me Me 269-272 2.16 (3H, s), 2.66 (3H, s), 6.72 (1H, d,(dec.) J=8.1 Hz), 6.93 (1H, d, J=8.1 Hz), 9.64 (1H, br s), 11.05 (1H,s), 12.14 (1H, br s)

EXAMPLE 2 OF REFERENCE

[0117]

3-Formyl-4-hydroxyindole-1-carboxylic Acid tert-butyl Ester (2-1)(R⁷═R¹¹═H)

[0118] A mixture of the 3-formyl-4-hydroxyindole (1-1) 323 mg,di-tert-butyldicarbonate 458 mg, dimethylaminopyridine 12.5 mg andacetonitrile 25 ml was stirred under cooling in ice for 3 h. The solventwas removed under reduced pressure and the residue obtained wasrecrystallized from acetone-isopropyl ether to give the titled compoundas pale yellow crystals, m.p. 159-161° C.(dec.), 389 mg. Yield 74%.

[0119]¹H-NMR(CDCl₃): 1.71 (9H, s), 6.84 (1H, dd, J=8.1, 0.9 Hz), 7.31(1H, t, J=8.1 Hz), 7.61 (1H, dd, J=8.1, 0.9 Hz), 8.25 (1H, s), 9.76 (1H,d, J=0.6 Hz), 10.13 (1H, s).

[0120] Following compounds were obtained, according to the similartreatment. Comp m.p. No R⁷ R¹¹ (° C.) ¹H-NMR (CDCl₃) 2-2 Ph H 154-1551.26 (9H, s), 6.86 (1H, dd, J=8.4, (dec.) 0.9 Hz), 7.33 (1H, t, J=8.4Hz), 7.43-7.53 (5H, m), 7.66 (1H, dd, J=8.4, 0.9 Hz), 9.36 (1H, s),10.64 (1H, s) 2-3 Me Me 177-179 1.71 (9H, s), 2.30 (3H, s), 2.88 (3H,s), (dec.) 7.09 (1H, d, J=8.4 Hz), 7.39 (1H, d, J=8.4 Hz), 9.90 (1H, brs), 10.92 (1H, s)

EXAMPLE 3 OF REFERENCE

[0121]

5-Bromo-3-formyl-4-hydroxyindole-1-carboxylic Acid tert-butyl Ester(2-4)

[0122] Compound (2-1) 26.1 g was suspended in dry tetrahydrofuran 260 mland chloroform 260 ml. Pyridinium bromide perbromide 33.6 g was added tothe suspension under cooling in ice and the mixture was stirred at roomtemperature for 4.5 h. An aqueous sodium hydrogen carbonate 16.77 gsolution was added to the reaction mixtures, which were extracted withchloroform. The extracts were washed with water, dried over anhydrousmagnesium sulfate, concentrated up to the deposition of crystals anddiluted with isopropanol. Appeared crystals were collected by filtrationto give the titled compound as yellow crystals. 29.1 g. Yield 86%. m.p.239-242° C.(dec.)

[0123]¹H-NMR(CDCl₃): 1.71 (9H, s), 7.52 (2H, s), 8.24 (1H, s), 9.75 (1H,s), 10.91 (1H, br s).

[0124] (Scheme of reactions, Examples 1-5)

EXAMPLE 1 7H-6-Oxa-2-azabenzo[c,d]azulene-2,8-dicarboxylic Acid2-tert-butyl Ester 8-methyl Ester (3-1) (R⁷═R¹¹═H) Method 1

[0125] 60% Sodium hydride 23.0 mg was suspended in dry tetrahydrofuran 4ml. Compound (2-1) 123 mg and trimethyl-2-phosphonoacrylate 116 μl wereadded with cooling in ice under nitrogen atmosphere and the mixture wasstirred for 19 h. Water was added to the mixture with cooling in ice andthe mixture was extracted with ethyl acetate. The extracts were washedwith water, dried over anhydrous magnesium sulfate and chromatographedon silica gel 25 g in ethyl acetate:hexane (1:10) to give the titledcompound (3-1) as colorless crystals, 46 mg. Yield 30%.

[0126]¹H-NMR(CDCl₃): 1.69 (9H, s), 3.84 (3H, s), 5.06 (2H, s), 6.85 (1H,dd, J=7.5, 0.6 Hz), 7.24 (1H, t, J=7.5 Hz), 7.74 (1H, s), 7.77 (1H, d,J=7.5 Hz), 8.00 (1H, s).

Method 2

[0127] Compound (2-1) 140 mg, 1,4-diazabicyclo[2.2.2]octane 70 mg wassuspended in methyl acrylate 1.4 ml and the suspension was stirred atroom temperature for 4 days. Ethyl acetate was added to the reactionmixtures and the insoluble materials were filtered off. The filtrate wasconcentrated under reduced pressure and chromatographed on silica gel 25g in ethyl acetate:hexane (1:10) to give titled compound (3-1) ascolorless crystals 59 mg. Yield 34%.

Method 3 (a)4-Hydroxy-3-(1-hydroxy-2-methoxycarbonylallyl)indole-1-carboxylic Acidtert-butyl Ester (4-1) (R⁷═R¹¹═H)

[0128] Compound (2-1) 140 mg and 1,4-diazabicyclo[2.2.2]octane 70 mgwere suspended in methyl acrylate 1.4 ml with cooling in ice and thesuspension was stirred at 4° C. for 24 h. The reaction mixtures waschromatographed on silica gel in ethyl acetate:hexane several times togive the titled compound (4-1) as a colorless oil 178 mg. Yield 96%.

[0129]¹H-NMR (CDCl₃): 1.66 (9H, s), 3.86 (3H, s), 5.05 (1H, br s), 5.63(1H, s), 5.81 (1H, s), 6.39 (1H, s), 6.78 (1H, dd, J=8.1, 0.9 Hz), 7.24(1H, t, J=8.1 Hz), 7.31 (1H, s), 7.67 (1H, d, J=8.1 Hz), 9.10 (1H, brs).

[0130] Following compounds were obtained, according to the similartreatment. Comp m.p. No R⁷ R¹¹ (° C.) ¹H-NMR (CDCl₃) 4-2 Ph H 121-1221.21 (9H, s), 3.82 (3H, s), 5.01 (1H, br s), 5.51 (2H, s), 6.35 (1H, s),6.81 (1H, dd, J=7.8, 0.6 Hz), 7.28 (1H, t, J=8.4 Hz), 7.38-7.40 (5H, m),7.83 (1H, dd, J=8.4, 0.6 Hz), 9.14 (1H, s) 4-3 Me Me 155-156.5 1.68 (9H,s), 2.29 (3H, s), 2.48 (3H, s), 3.87 (3H, s), 5.14 (1H, br s), 5.37 (1H,s), 5.96 (1H, s), 6.30 (1H, s), 7.05 (1H, d, J=8.4 Hz), 7.56 (1H, d,J=8.4 Hz), 9.27 (1H, s) 4-4 H Br Colorless 1.66 (9H, s), 3.85 (3H, s),5.13 (1H, d, oil J=5.4 Hz), 5.62 (1H, s), 5.82 (1H, d, J=5.4 Hz), 6.39(1H, s), 7.32 (1H, s), 7.44 (1H, d, J=8.7 Hz), 7.57 (1H, d, J=8.7 Hz),9.59 (1H, br s)

(b) 7H-6-Oxa-2-azabenzo[c,d]azulene-2,8-dicarboxylic Acid 2-tert-butylEster 8-methyl Ester (3-1)

[0131] Triethylamine 20.1 mg, 1,1′-(azodicarbonyl)-dipiperidine 42.0 mgand triphenylphosphine 43.9 mg were dissolved in dry tetrahydrofuran 1ml. Compound (4-1) 37 mg was added to the solution with cooling in iceunder nitrogen. The mixture was stirred at room temperature for 17 h.Water was added with cooling in ice and the reaction mixture wasextracted with ethyl acetate. The extracts were washed with water, driedover anhydrous magnesium sulfate and chromatographed on silica gel 15 gin ethyl acetate:hexane (1:3) to give titled compound (3-1) as colorlesscrystals, 17. mg. Yield 48%.

(C) 7H-6-Oxa-2-azabenzo[c,d]azulene-2,8-dicarboxylic Acid 2-tert-butylEster 8-methyl Ester (3-1) (R⁷═R¹¹═H)

[0132] Acetic anhydride 0.38 ml was added to a solution of compound(4-1) 1.32 g in pyridine 13.1 ml with cooling in ice under nitrogen. Themixture was stirred at that temperature for 1 h The solvent was removedby distillation under reduced pressure and the residue obtained waschromatographed on silica gel 60 g in ethyl acetate:hexane (1:3) to givea yellow oil 860 mg. The oily compound 747 mg was dissolved in dioxane 7ml and potassium carbonate 530.5 mg was added. The mixture was stirredat 80° C. for 6 h, filtered through cerite and chromatographed on silicagel 40 g in ethyl acetate:hexane (1:10) to give the titled compound(3-1) as colorless crystals, 501 mg. Yield 40%, m.p. 124-126° C.(recrystallized from isopropanol)

[0133] Following compounds were obtained, according to the similartreatment. Comp m.p. No R⁷ R¹¹ (° C.) ¹H-NMR (CDCl₃) 3-2 Ph H 151-1521.26 (9H, s), 3.75 (3H, s), 5.08 (2H, s), 6.87 (1H, dd, J=8.1, 0.9 Hz),7.27 (1H, t, J=8.1 Hz), 7.35-7.49 (5H, m), 7.65 (1H, s), 7.87 (1H, dd,J=8.1, 0.9 Hz) 3-3 Me Me 112-114 1.69 (9H, s), 2.31 (3H, s), 2.70 (3H,s), 3.84 (3H, s), 5.03 (2H, s), 7.04 (1H, d, J=8.4 Hz), 7.61 (1H, d,J=8.4 Hz), 8.07 (1H, s) 3-4 H Br 160-161 1.68 (9H, s), 3.84 (3H, s),5.14 (2H, s), 7.46 (1H, d, J=9.0 Hz), 7.68 (1H, d, J=9.0 Hz), 7.74 (1H,s), 7.99 (1H, s)

Method 4)4-Hydroxy-3-(1-hydroxy-2-methoxycarbonylallyl)-2,5-dimethylindole-1-carboxylicAcid tert-butyl Ester (4-3) (R⁷═R¹¹═H)

[0134] Diisobutylaluminumhydride (0.9 mol/l hexane solution) 50 ml wasadded to a mixture of hexamethylphosphorous triamide (8.96) g and drytetrahydrofuran 80 ml with cooling in ice under a nitrogen atmosphere.The mixture was stirred for 30 min. Methyl propiorate 3.78 g was addedand he mixture was stirred for 1 h with cooling in ice. Compound (2-3)4.36 g was added to the reaction mixture, which was stirred for 10 minand then at room temperature for 2 h. 1N-HCl 50 ml was added withcooling in ice and the mixture was extracted with ethyl acetate. Theextracts were washed with 1N-HCl, water, brine and dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueobtained was chromatographed on silica gel 130 g in ethyl acetate:hexane(1:4) to give colorless crystals which were recrystallized from ethylacetate-hexane to give the titled compound, 4.47 g. Yield 80%, m.p.155-156.5° C.

EXAMPLE 2 2,7-Dihydro-6-oxa-2-azabenzo[c,d]azulene-8-carboxylic Acid(5-1) (R⁷═R¹¹═H)

[0135] The above obtained compound (3-1) 1.01 g was dissolved intetrahydrofuran 15 ml and 1 N sodium hydroxide 15 ml was added to thesolution. The mixture was stirred for 1 h. Methanol 7.5 ml was added.The mixture was stirred at 50° C. for 3 h, acidified with 2N-HCl 7.5 mlto weakly acidic with cooling in ice and extracted with ether. Theextracts were washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure to give a yellow solid, whichwas recrystallized from methanol to give the titled compound (5-1), m.p.230° C.(dec.) as yellow crystals, 450 mg. From the mother liquor, thesecond crop 134 mg was obtained by crystallization from isopropanol.Yield 88%.

[0136]¹H-NMR (CD₃OD): 4.98 (2H, s), 6.60 (1H, m), 7.02-7.08 (2H, m),7.55 (1H, s), 8.19 (1H, s).

[0137] Following compounds were obtained, according to the similartreatment. Compd m.p. No R⁷ R¹¹ (° C). ¹H-NMR (DMSO-d₆) 5-2 Ph H 218-2204.98 (2H, s), 6.59-6.60 (1H, m), (dec.) 7.06-7.13 (2H, m), 7.51-7.68(5H, m), 8.05 (1H, s), 12.27 (1H, br s) 5-3 Me ME 203-206 2.20 (3H, s),2.48 (3H, s), 4.87 (2H, s), (dec.) 6.84-6.89 (2H), 8.03 (1H, s), 11.69(1H, s), 12.03 (1H, br s) 5-4 H Br 210-215 4.97 (2H, s), 7.07 (1H, d,J=8.4 Hz), (dec.) 7.27 (1H, d, J=8.7 Hz), 7.83 (1H, s), 8.09 (1H, s),12.07 (1H, s)

EXAMPLE 3 (2,7-Dihydro-6-oxa-2-azabenzo[c,d]azulen-8-yl)carbamic Acidtert-butyl Ester (6-1) (R⁷═H)

[0138] Triethylamine 0.38 ml and chloroethyl carbonate 0.26 ml wereadded to a solution of the compound obtained by Ex. 2 (5-1) 530 mg indry tetrahydrofuran 5 ml with cooling in ice-methanol bath and themixture was stirred for 30 min. Then an aqueous solution of sodium azide320 mg/water 2 ml was added dropwise and the mixture was stirred for 4 hwith cooling in ice-methanol bath. Water was added and the reactionmixture was extracted with ethyl acetate. The extracts were washed withbrine and dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give a yellow solid. The residue obtained wassuspended in toluene 20 ml and heated under reflux at 125° C. for 20 minand concentrated under reduced pressure. The residue obtained was againsuspended in t-butanol 20 ml, heated at 100° C. for 2.5 h andconcentrated under reduced pressure. The residue obtained waschromatographed on silica gel 50 g in ethyl acetate:hexane (1:3) to givebrown crystals, which was recrystallized from ether-petrolether to givethe titled compound (6-1) m.p. 125-130° C. (dec.) as pale browncrystals, 436 mg. Yield 62%.

[0139]¹H-NMR (CDCl₃): 1.50 (9H, s), 4.76 (2H, s), 6.01 (1H, br s), 6.64(1H, dd, J=7.2, 1.2 Hz), 6.98-7.12 (3H, m), 8.17 (1H, br s).

[0140] Following compounds were obtained, according to the similartreatment. Compd m.p. No R⁷ (° C.) ¹H-NMR (CDCl₃) 6-2 Ph 201-202 1.49(9H, s), 4.90 (2H, br s), 6.11 (1H, br s), (dec.) 6.67 (1H, m),6.88-7.41 (5H, m), 7.49 (1H, m), 7.59 (1H, d, J=8.4 Hz), 8.24 (1H, br s)

EXAMPLE 4 (2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[c,d]azulen-8-yl)carbamicAcid tert-butyl Ester (7-1) (R⁷═H)

[0141] 5% Pd/C 100 mg was added to a solution of the compound obtainedin Ex. 3 460 mg in methanol 10 ml. The mixture was stirred in a hydrogenatmosphere for 1.5 h. The catalyst was filtered off and the filtrate wasconcentrated under reduced pressure. The residue obtained waschromatographed on silica gel in ethyl acetate:hexane (1:3) to give thetitled compound (7-1) as a reddish oil, 390 mg. Yield 84%.

[0142]¹H-NMR (CDCl₃): 1.41 (9H, s), 2.98-3.10 (1H, m), 3.26-3.38 (1H,m), 4.23 (1H, d, J=12.0 Hz), 4.27-4.40 (1H, m), 4.48-4.58 (1H, m), 6.67(1H, dd, J=7.2, 0.9 Hz), 6.98 (1H, br s), 7.02 (1H, dd, J=7.2, 0.9 Hz),7.09 (1H, t, J=7.2 Hz), 8.13 (1H, br s).

[0143] Following compounds were obtained, according to the similartreatment. Compd m.p. No R⁷ (° C.) ¹H-NMR (CDCl₃) 7-2 Ph 188-189 1.38(9H, s), 3.18 (1H, m), 3.43 (1H, m), 4.29 (1H, d, J=12.0 Hz), 4.39 (1H,m), 4.56 (1H, m), 5.08 (1H, br s), 6.70 (1H, m), 7.04 (1H, m), 7.11 (1H,t, J=7.8 Hz), 7.34-7.55 (5H, m), 8.28 (1H, br s)

EXAMPLE 5 2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[c,d]azulen-8-ylamine (8-1)

[0144] The compound obtained in Ex 4 (7-1) 262 mg was dissolved in ethylacetate 3 ml. A solution of 4 N HCl/ethyl acetate 2 ml was added to thesolution with cooling in ice and the mixture was stirred at roomtemperature for 3 h. Furthermore, 4N-HCl/ethyl acetate 1 ml was addedand the mixture was stirred at room temperature for 1 h. After thevolatile materials were remove by distillation under reduced pressure upto the half volume, the mixture was diluted with ethyl acetate 10 ml. Anaqueous saturated sodium hydrogen solution carbonate was added toalkaline with cooling in ice. The mixture was extracted with ethylacetate. The extracts were washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to give abrown oily residue, which was chromatographed on aluminum oxide 40 g inmethanol:chloroform (3:97) to give the titled compound (8-1) as browncrystals, 144 mg. Yield 84%.

[0145] Further, this oil was recrystallized from isopropanol to give thetitled compound (8-1) as gray crystals, 60 mg. m.p. 172-173° C.

[0146]¹H-NMR (CD₃OD): 2.84-2.93 (1H, ddd, J=15.6, 8.7, 1.5 Hz),3.17-3.25 (1H, m), 3.36-3.43 (1H, m), 4.12-4.25 (2H, m), 6.43-6.50 (1H,m), 6.89-7.00 (3H, m).

[0147] Following compounds were obtained, according to the similartreatment. Compd m.p. No R⁷ (° C.) ¹H-NMR (CDCl₃) 8-2 Ph 189-191 3.09(1H, dd, J=15.6, 8.1 Hz), 3.29 (1H, dd, J=15.6, 3.6 Hz), 3.59 (1H, m),4.27-4.36 (2H, m), 6.67 (1H, m), 7.01 (1H, m), 7.10 (1H, t, J=8.1 Hz),7.34-7.59 (5H, m), 8.25 (1H, br s)

[0148] Scheme of reactions, Examples 6-10 are shown in below.

EXAMPLE 68-Hydroxy-2,7-dihydro-6-oxa-2-azabenzo[c,d]azulene-9-carbonitrile (10)

[0149] Compound (9) 200 mg was dissolved in dry tetrahydrofuran 10 ml.60% Sodium hydride 72 mg was added to the solution with cooling in iceand the mixture was stirred at room temperature for 2.5 h. After excesssodium hydride was decomposed with ethanol with cooling in ice, 2 N-HCl1.5 ml was added. The mixture was extracted with ether. The extractswere washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on silica gel 4 g in ether to give an eluent 187 mgwhich was again chromatographed on silica gel 5 g in ether to give thetitled compound (10) as reddish orange crystals, 132 mg. Yield 79.5%.

[0150]¹H-NMR (CDCl₃): 4.80 (2H, s), 6.52 (1H, dd, J=7.5, 0.9 Hz), 6.99(1H, t, J=7.5 Hz), 7.06 (1H, dd, J=7.5, 0.9 Hz), 7.24 (1H, d, J=2.7 Hz),11.07 (1H, s), 11.39 (1H, s).

EXAMPLE 7 (1) 3-Ethoxycarbonylmethyl-1H-indol-4-yloxy)acetic Acid EthylEster (11)

[0151] Compound (9) 1.49 g was dissolved in 95% ethanol 45 ml.Concentrated sulfuric acid 4.5 ml was added to the solution. The mixturewas heated under reflux for 40 h. After the solvent was removed underreduced pressure, ice-water was added to the mixture, which wasextracted with chloroform. The extracts were washed with water driedover anhydrous magnesium sulfate and chromatographed on silica gel 37 gin chloroform. The eluent 1.497 g was recrystallized fromacetone-isopropyl ether to give the titled compound (11) as pale graycrystals, 1.304 g, m.p. 90-91.5° C. Yield 70.1%.

[0152]¹H-NMR (CDCl₃): 1.26 (3H, t, J=7.2 Hz), 1.31 (3H, t, J=7.2 Hz),4.05 (2H, s), 4.18 (2H, q, J=7.2 Hz), 4.28 (2H, q, J=7.2 Hz), 4.69 (2H,s), 6.36 (1H, dd, J=7.2, 0.9 Hz), 6.97-7.07 (3H, m), 8.07(1H, br s).

(2) 8-Hydroxy-2,7-dihydro-6-oxa-2-azabenzo[c,d]azulene-9-carboxylic Acidethyl-ester (12)

[0153] Compound (11) 754 mg was dissolved in dry tetrahydrofuran 20 ml.60% Sodium hydride 217 mg was added to the solution of with cooling inice. The mixture was stirred at room temperature for 1 h. To theice-cold reaction mixture, ethanol 0.5 ml was added and the 2N HCl 3 mlwas added to acidify. The mixture was extracted with ether. The extractswere washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on silica gel 45 g in chloroform. The eluent 198 mg wasrecrystallized from ether-isopropyl ether to give the titled compound(12) as colorless crystals 195 mg, m.p. 136-137° C. Yield 30.5%.

[0154]¹H-NMR (CDCl₃): 1.44 (3H, t, J=7.2 Hz), 4.42 (2H, q, J=7.2 Hz),4.75 (2H, s), 6.56-6.71 (1H, m), 7.02-7.09 (2H, m), 7.50 (1H, d, J=2.7Hz), 8.20 (1H, br s), 13.02 (1H, s).

EXAMPLE 88-Methoxyl-2,7-dihydro-6-oxa-2-azabenzo[c,d]azulene-9-carboxylic AcidEthyl Ester (13)

[0155] A mixture of the compound obtained in Ex. 7 (12) 100 mg, methyliodide 0.031 ml and potassium carbonate 9 mg in dimethylformamide 3 mlwas stirred at room temperature for 15 h. Water was added and themixture was extracted with ether. The extracts were washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue obtained was chromatographed on silica gel 6 g inchloroform. The eluent 102 mg was recrystallized from acetone-ether togive the titled compound (13) as colorless crystals 67 mg, m.p. 183-184°C. Yield 63.8%.

[0156]¹H-NMR (CDCl₃): 1.24-1.29 (3H, m), 1.82 (3H, s), 4.16-4.35 (2H,m), 4.49 (1H, d, J=17.4 Hz), 5.02 (1H, d, J=17.4 Hz), 6.73-6.79 (1H, m),6.96-6.97(1H, m), 7.02-7.13 (2H, m), 8.35 (1H, br s).

EXAMPLE 9 (1)4-Ethoxycarbonylmethoxy-3-ethoxycarbonylmethyl-indole-1-carboxylic Acidtert-butyl Ester (14)

[0157] Compound (11) 1.40 g and di-tert-butyldicarbonate 1.05 g weredissolved in tetrahydrofuran 20 ml and 4-dimethylaminopyridine 28 mg wasadded. The mixture was allowed to stand at room temperature overnightand concentrated under reduced pressure to remove tetrahydrofurane. Theresidue obtained was dissolved in toluene and chromatographed on silicagel 10 g in 5% ethyl acetate-toluene to give the titled compound (14) asa colorless oil, 1.789 g. Yield 96.2%.

[0158]¹H-NMR (CDCl₃): 1.26 (3H, t, J=7.2 Hz), 1.30 (3H, t, J=7.2 Hz),1.65 (9H, s), 3.96 (2H, s), 4.18 (2H, q, J=7.2 Hz), 4.27 (2H, q, J=7.2Hz), 4.67 (2H, s), 6.52 (1H, d, J=8.1 Hz), 7.18 (1H, t, J=8.1 Hz), 7.42(1H, s), 7.80 (1H, d, J=8.1 Hz).

(2) 8-Hydroxy-7H-6-oxa-2-azabenzo[c,d]azulene-2,9-dicarboxlic Acid2-tert-butyl Ester 9-ethyl Ester (15)

[0159] Compound (14) 953 mg was dissolved in dry tetrahydrofuran 15 mland 1.0 M solution of lithium bistrimethylsilylamide-tetrahydrofuran 3.5ml was added to the solution with cooling in ice. The mixture wasstirred at room temperature for 30 min. A solution of ammonium chloride375 mg in water 5 ml was added with cooling in ice. The mixture wasextracted with ether. The extracts were washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue obtained was chromatographed on silica gel 30 g in chloroform.The eluent 259 mg was recrystallized from ether-isopropyl ether to givethe titled compound (15) as colorless crystals, m.p.139.5-140.5° C., 236mg. Yield 28.0%.

[0160]¹H-NMR (CDCl₃): 1.47 (3H, t, J=7.1 Hz), 1.68 (9H, s), 4.43 (2H, q,J=7.1 Hz), 4.73 (2H, s), 6.80 (1H, d, J=8.1 Hz), 7.18 (1H, t, J=8.1 Hz),7.83 (1H, d, J=8.1 Hz), 7.87 (1H, s), 13.27 (1H, s).

EXAMPLE 10 (1)[3-Ethoxycarbonylmethyl-1-(toluene-4-sulfonyl)-1H-indol-4-yloxy]aceticAcid Ethyl Ester (16)

[0161] Compound (11) 305 mg was dissolved in dry tetrahydrofuran 20 ml.1.0 M Solution of lithium bistrimethylsilylamide-tetrahydrofuran 1.1 mlwas added to the solution with cooling in dry ice-acetone bath at −70°C. After the mixture was stirred for 10 min, a solution ofp-toluenesulfonyl chloride 229 mg in tetrahydrofuran 3 ml was added atthat temperature. The mixture was stirred at room temperature for 2 h. Asolution of ammonium chloride 59 mg in water 1 ml was added to themixture, which was concentrated under reduced pressure to removetetrahydrofuran. Water was added. The mixture was extracted withchloroform. The extracts were washed with water dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueobtained was chromatographed on silica gel 17 g in chloroform to givethe titled compound (16) as a colorless oil 231 mg. Yield 50.2%.

[0162]¹H-NMR (CDCl₃): 1.24 (3H, t, J=7.2 Hz), 1.28 (3H, t, J=7.2 Hz),2.34 (3H, s), 3.94 (2H, s), 4.16 (2H, q, J=7.2 Hz), 4.25 (2H, q, J=7.2Hz), 4.62 (2H, s), 6.49 (1H, d, J=8.1 Hz), 7.17 (1H, t, J=8.1 Hz), 7.21(2H, d, J=8.7 Hz), 7.44 (2H, d, J=8.7 Hz), 7.60 (1H, d, J=8.1 Hz), 7.74(2H, d, J=8.7 Hz).

(2)8-Hydroxy-2-(toluene-4-sulfonyl)-2,7-dihydro-6-oxa-2-azabenzo[c,d]-azulene-9-carboxlicAcid Ethyl Ester (17)

[0163] Compound (16) 228 mg was dissolved in dry tetrahydrofuran 10 mland 1.0 M solution of lithium bistrimethylsilylamide tetrahydrofuran1.05 ml was added to the solution with cooling in ice. The mixture wasstirred for 20 min. A solution of ammonium chloride 112 mg in water 1 mlwas added to the mixture, which was acidified with dilute hydrochloricacid. The mixture was extracted with ether. The extracts were washedwith brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue obtained 279 mg was chromatographedon silica gel 10 g in toluene to give the titled compound (17) as a paleyellow oil 61 mg. Yield 29.8%.

[0164]¹H-NMR (CDCl₃): 1.50 (3H, t, J=7.2 Hz), 2.35 (3H, s), 4.45 (2H, q,J=7.2 Hz), 4.68 (2H, s), 6.78 (1H, dd, J=7.8, 0.9 Hz), 7.17 (1H, t,J=7.8 Hz), 7.23 (2H, d, J=8.1 Hz), 7.67 (1H, dd, J=7.8, 0.9 Hz), 7.77(2H, d, J=8.7 Hz) 7.80 (1H, s), 13.30 (1H, s).

[0165] (Scheme of reactions, Examples 11-16)

EXAMPLE 11 2,9-Dihydro-6-oxa-2-azabenzo[cd]azulen-8-one (18-1)(R⁷═R¹¹═H)

[0166] Triethylamine 10 ml and ethyl chlorocarbonate 5.6 ml were addedto a solution of compound (5-1) 14.85 g in dry tetrahydrofuran 148 mlwith cooling in ice-methanol bath. The mixture was stirred at thattemperature for 30 min. Then, a solution sodium azide 8.97 g in water 59ml was added dropwise. The mixture was stirred with cooling in ice for 4h. To the reaction mixtures water was added. The mixture was extractedwith ethyl acetate. The extracts were washed with brine, dried overanhydrous magnesium sulfate, concentrated under reduced pressure to givea yellow solid. The residue obtained was suspended in dioxane 280 ml.After the suspension was heated under reflux for 20 min, 1N HCl 58.3 mlwas added with cooling in ice. Again, the mixture was heated underreflux for 20 min and cooled in ice-bath. Water was added. The mixturewas extracted with ether. The extracts were washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue obtained was chromatographed on silica gel 150 gin ethyl acetate:hexane (1:4) to give brown crystals, which wasrecrystallized from ether-petroleum ether to give the titled compound7.94 g, m.p. 128-129° C. Yield 61%.

[0167]¹H-NMR(CDCl₃): 4.11 (2H, d, J=0.6 Hz), 4.69 (2H, s), 6.72-6.79(1H, m), 6.92-6.95 (1H, m), 7.07-7.14 (2H, m), 8.12 (1H, br s).

[0168] Following compounds were obtained, according to the similartreatment. Compd m.p. No R⁷ R¹¹ (° C). ¹H-NMR (CDCl₃) 18-2 Me ME 136-1392.32 (3H, s), 2.33 (3H, s), 3.99 (2H, s), 4.66 (2H, s), 6.89 (1H, d,J=8.4 Hz), 6.92 (1H, d, J=8.4 Hz), 7.77 (1H, br s) 18-3 H Br 137-1384.09 (2H, d, J=1.2 Hz), 4.75 (2H, s), 6.95 (1H, m), 7.01 (1H, d, J=8.7Hz), 7.27 (1H, d, J=8.7 Hz), 8.14 1H, br s)

EXAMPLE 12Dimethyl-(2,7,8,9-tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)amine(19-1) (R⁷═R¹¹═H; R¹⁶═R¹⁷═Me)

[0169] Dimethylamine (2 mol/tetrahydrofuran solution), compound (18-1)690 mg, sodium triacetoxyborohydride 1.17 g and acetic acid 226 mg weredissolved in tetrahydrofuran 28 ml with cooling in ice. The mixture wasstirred at room temperature for 1 h and allowed stand overnight. To thereaction mixture, ice-water and an aqueous sodium hydrogen carbonatesolution were added. The mixture was extracted with ether. The extractswere washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on aluminum oxide 30 g in chloroform:methanol (50:1) togive the titled compound as colorless crystals 689 mg. Yield 86%. Thiswas recrystallized from ethyl acetate-hexane to give colorless crystals,m.p. 131-132.5° C.

[0170]¹H-NMR(CDCl₃): 2.42 (6H, s), 2.93-3.24 (3H, m), 4.15 (1H, dd,J=12.3, 6.6 Hz), 4.55 (1H, dd, J=12.3, 1.5 Hz), 6.62 (1H, dd, J=6.6, 0.9Hz), 6.95-7.09 (3H, m), 8.14 (1H, br s).

[0171] Following compounds were obtained, according to the similartreatment. Compd No R⁷ R¹¹ R¹⁶ R¹⁷ m.p. (° C.) ¹H-NMR (CDCl₃) 19-2 H H HMe 112-116 2.56 (3H, s), 2.99-3.22 (3H, in), oxalate 4.27-4.38 (2H, m),6.65 (1H, d, J= 7.5 Hz), 6.96-7.09 (3H, m), 8.24 (1H, br s) 19-3 H H HnPr 137-139 0.93 (3H, t, J=7.5 Hz), 1.54 (2H, sex, J=7.5 Hz), 2.62-2.80(2H, m), 2.92-3.02 (1H, m), 3.14-3.25 (2H, m), 4.19-4.30 (2H, m),6.44-6.50 (1H, m), 6.90-7.02 (3H, m) CD₃OD 19-4 H H Et Et 123-124 1.12(6H, t, J=7.5 Hz), 2.69 (4H, q, J=7.5 Hz), 2.90-3.00 (1H, m), 3.20-3.30(2H, m), 4.08 (1H, dd, J= 11.7, 6.3 Hz), 4.53 (1H, dd, J= 11.7, 2.1 Hz),6.41-6.48 (1H, m), 6.88-6.95 (2H, m), 7.01-7.03 (1H, m) CD₃OD 19-5 H HNPr nPr 60-61 0.90 (6H, t, J=7.5 Hz), 1.40-1.60 (4H, m), 2.40-2.60 (4H,m), 2.90- 3.01 (1H, m), 3.15-3.35 (2H, m), 4.09 (1H, dd, J=12.3, 6.9Hz), 4.61 (1H, dd, J=12.3, 1.8 Hz), 6.61 (1H, d, J=7.5 Hz), 6.95-6.98(2H, m), 7.06 (1H, t, J=7.5 Hz), 8.06 (1H, br s) 19-6 H H H cyclohexyl141-142 1.00-2.02 (10H, m), 2.64-2.74 (1H, m), 2.98 (1H, ddd, J=15.3,8.4, 1.2 Hz), 3.14 (1H, dd, J=15.3, 3.6 Hz), 3.39-3.47 (1H, m),4.23-4.32 (2H, m), 6.63 (1H, dd, J=7.5, 0.9 Hz), 6.95-6.99 (2H, m), 7.07(1H, t, J=7.5 Hz), 8.11 (1H, br s) 19-7 H H H allyl 112-113 3.00-3.18(2H, m), 3.28-3.49 (1H, m), 4.27-4.38 (2H, m), 5.08-5.13 (1H, m),5.18-5.26 (1H, m), 5.86- 5.99 (1H, m), 6.64 (1H, dd, J= 7.8, 1.2 Hz),6.95-7.00 (2H, m), 7.07 (1H, t, J=7.8 Hz), 8.11 (1H, br s) 19-8 H H HiPr 133-135 1.10 (3H, d, J=6.0 Hz), 1.11 (3H, d, J=6.0 Hz), 2.97-3.17(3H, m), 3.35-3.42 (1H, m), 4.25-4.37 (2H, m), 6.64 (1H, dd, J=7.5, 0.9Hz), 6.95-7.00 (2H, m), 7.07 (1H, t, J=7.5 Hz), 8.10 (1H, br s) 19-9 H HH

104-106 2.83 (2H, t, J=7.5 Hz), 2.95-3.17 (4H, m), 3.26-3.33 (1H, m),4.29 (2H, d, J=3.6 Hz), 6.62 (1H, d, J=7.5 Hz), 6.93-7.00 (2H, m), 7.07(1H, t, J=7.8 Hz), 7.18-7.30 (5H, m), 8.08 (1H, br s) 19-10 H H

137-139 1.80-1.89 (4H, m), 2.70-3.04 (6H, m), 3.37(1H, d, J=14.4 Hz),4.17 (1H, dd, J=12.3, 6.3 Hz), 4.59 (1H, dd, J=12.3, 2.1 Hz), 6.61 (1H,dd, J=7.5, 0.9 Hz), 6.95-6.99 (2H, m), 7.06 (1H, t, J=7.8 Hz), 8.10 (1H,br s) 19-11 H H

115-125 (dec.) oxalate 1.45-1.75 (6H, m), 2.50-2.80 (4H, m), 2.94-3.12(2H, m), 3.24-3.31 (1H, m), 4.10 (1H, dd, J=12.0, 6.3 Hz), 4.63 (1H, dd,J=12.0, 1.8 Hz), 6.61 (1H, dd, J=7.8, 0.9 Hz), 6.94-6.98 (2H, m), 7.06(1H, t, J=7.8 Hz), 8.10 (1H, br s) 19-12 H H

183-184 (dec.) oxalate 2.32 (3H, s), 2.40-2.60 (4H, m), 2.62-2.73 (2H,m), 2.80-2.90 (2H, m), 2.95-3.11 (2H, m), 3.22-3.30 (1H, m), 4.12 (1H,dd, J=12.3, 6.3 Hz), 4.60 (1H, dd, J=12.3, 2.1 Hz), 6.61 (1H, dd, J=7.8,0.9 Hz), 6.95-6.99 (2H, m), 7.06 (1H, t, J=7.8 Hz), 8.12 (1H, br s)19-13 H H

207-208 2.46-2.56 (2H, m), 2.62-2.72 (2H, m), 2.76-2.98 (2H, m),3.08-3.18 (1H, m), 3.53-3.62 (4H, m), 4.06 (1H, dd, J=12.3, 6.6 Hz),4.45 (1H, d, J=12.3 Hz), 6.40 (1H, dd, J=6.6, 2.1 Hz), 6.86-6.94 (2H,m), 7.11 (1H, d, J=1.8 Hz), 10.95 (1H, br s) DMSO-d₆ 19-14 H H HCH₂CH₂OH 154-157 2.85-3.11 (4H, m), 3.25-3.30 (2H, (dec.) m), 3.62 (2H,t, J=5.4 Hz), 4.26- oxalate 4.42 (2H, m), 6.64 (1H, dd, J=7.5, 0.9 Hz),6.96-7.10 (3H, m), 8.16 (1H, br s) 19-15 H Br H Me

2.58 (3H, s), 2.91-3.22 (3H, m), 4.34(1H, dd, J=12.6, 6.9 Hz), 4.44(1H,d, J=12.6 Hz), 6.86 (1H, d, J=8.4 Hz), 6.97 (1H, m), 7.28 (1H, d, J=8.4Hz), 8.17 (1H, br s) 19-16 H Br Me Me 142-143 2.43 (6H, s), 2.92-3.23(3H, m), 4.22 (1H, dd, J=12.3, 6.9 Hz), 4.67 (1H, dd, J=12.3, 1.8 Hz),6.85 (1H, d, J=8.7 Hz), 6.98 (1H, m), 7.26 (1H, d, J=8.7 Hz), 8.13 (1H,br s) 19-17 Me Me Me Me 144-146 2.28 (3H, s), 2.34 (3H, s), 2.47 (6H,s), 2.82-3.11 (3H, m), 4.10 (1H, dd, J=12.0 Hz, 6.6 Hz), 4.58 (1H, d,J=12.0 Hz), 6.79 (1H, d, J=8.1 Hz), 6.87 (1H, d, J=8.1 Hz), 7.74 (1H, brs) 19-18 Me Me H Me 173-175 2.29 (3H, s), 2.31 (6H, s), 2.57 (3H, (dec.)s), 2.80-2.87 (1H, m), 2.97-3.03 oxalate (1H, m), 3.12-3.20 (1H, m),4.29- 4.32 (2H, m), 6.79 (1H, d, J=8.1 Hz), 6.87 (1H, d, J=8.1 Hz), 7.79(1H, br s), 19-19 H H H cyclopropyl 130-131 0.34-0.55 (4H, m), 2.27-2.34(1H, m), 3.02-3.18 (2H, m), 3.38-3.44 (1H, m), 4.33-4.44 (2H, m), 6.65(1H, dd, J=7.5, 0.9 Hz), 6.94-7.07 (3H, m), 8.27 (1H, br s) 19-20 H H HCH₂CF₃ 108-109 3.13 (2H, d, J=5.1 Hz), 3.27-3.44 (3H, m), 4.25 (1H, d,J=12.6 Hz), 4.40 (1H, dd, J=12.6, 6.9 Hz), 6.64 (1H, dd, J=8.1, 0.9 Hz),6.98 (1H, s), 7.00 (1H, dd, J=8.1, 0.9 Hz), 7.08 (1H, t, J=8.1 Hz), 8.10(1H, br s) 19-21 H H Me Et 122-124 1.13 (3H, t, J=7.2 Hz), 2.39 (3H, s),2.54-2.79 (2H, m), 2.97-3.27 (3H, m), 4.12 (1H, dd, J=12.3, 6.3 Hz),4.59 (1H, dd, J=12.3, 1.8 Hz), 6.62 (1H, dd, J=7.5, 0.9 Hz), 6.96-7.09(3H, m), 8.12 (1H, br s) 19-22 H H H Et 139-141 1.14 (3H, t, J=7.2 Hz),2.73-2.93 (2H, m), 3.00-3.19 (2H, m), 3.26- 3.33 (1H, m), 4.27-4.37 (1H,m), 6.64 (1H, dd, J=7.5, 0.9 Hz), 6.96-6.99 (2H, m), 7.07 (1H, t, J= 7.5Hz), 8.15 (1H, br s)

EXAMPLE 13 Method 1(2-Benzenesulfonyl-2,7,8,9-tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)dimethylamineOxalate (20-1) (R⁷═R¹¹═H)

[0172] 60% Sodium hydride 17 mg was added to a solution of compound(19-1) 75 mg in dry dimethylformamide 2.5 ml with cooling in ice. Themixture was stirred at 45° C. for 1 h. Benzenesulfonyl chloride 1 ml wasadded with cooling in ice. The mixture was stirred at room temperaturefor 21 h. Ice-water and an aqueous sodium hydrogen carbonate solutionwere added to the mixture, which was extracted with ether. The extractswere washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on aluminum oxide in chloroform:hexane (1:2) to give thetitled compound, 46 mg (yield 37%). This compound was treated with 1 eq.of oxalic acid to give the oxalic acid salt, which was recrystallizedfrom ether-ethanol to give colorless crystals. m.p. 106-109° C.(dec.).

[0173]¹H-NMR(CDCl₃): 2.36 (6H, s), 2.80-3.12 (3H, m), 4.13 (1H, dd,J=12.3, 6.6 Hz), 4.42 (1H, dd, J=12.3, 0.6 Hz), 6.75 (1H, d, J=8.1 Hz),7.14-7.20 (1H, m), 7.34 (1H, s), 7.41-7.61 (4H, m), 7.86-7.89 (2H, m)

[0174] Following compounds were obtained, according to the similartreatment. Comp No. R⁷ R⁸ R¹¹ m.p. ¹H-NMR (CDCl₃) 20-2 H COPh H 126-1292.40 (6H, s), 2.86-3.16 (3H, m), 4.20 (1H, (dec.) dd, J=12.3, 6.3 Hz),4.50 (1H, d, J= oxalate 12.3 Hz), 6.85 (1H, dd, J=7.2, 0.9 Hz), 7.06(1H, s), 7.23-7.28 (1H, m), 7.49-7.63 (3H, m), 7.71 (2H, dd, J=8.4, 1.8Hz), 8.04 (1H, dd, J=8.1, 0.9 Hz) 20-3 H CH₂Ph H 183-186 2.41 (6H, s),2.88-3.06 (2H, m), 3.15-3.22 (dec.) (1H, m), 4.15 (1H, dd, J=12.0, 6.3Hz), oxalate 4.54 (1H, dd, J=12.0, 1.8 Hz), 5.23 (2H, s) 6.61 (1H, dd,J=7.8, 0.6 Hz), 6.85- 6.89 (2H, m), 7.02-7.15 (3H, m), 7.25- 7.33 (3H,m) 20-4 H CH₂CONMe₂ H 119-124 2.40 (6H, s), 2.99 (3H, s), 3.04 (3H, s),(dec.) 2.88-3.22 (2H, m), 3.15-3.22 (1H, m), oxalate 4.13 (1H, dd,J=12.3, 6.6 Hz), 4.53 (1H, dd, J=12.3, 1.8 Hz), 4.82 (2H, s), 6.61 (1H,dd, J=8.1, 0.9 Hz), 6.79-7.10 (3H, m) 20-5 H

H 148-149 2.37 (6H, s), 2.89 (1H, m), 3.06-3.16 (2H, m), 4.15 (1H, dd,J=12.9, 6.9 Hz), 4.43 (1H, d, J=12.9 Hz), 6.71 (1H, dd, J=7.8, 0.6 Hz),7.10 (1H, t, J=8.1 Hz), 7.39-7.67 (5H ,m), 7.86-8.15 (3H, m), 8.76 (1H,d, J=8.7 Hz) 20-6 H

H 114-118 (dec.) oxalate 2.36 (6H, s), 2.81-3.11 (3H, m), 4.14 (1H, dd,J=12.6, 6.6 Hz), 4.43 (1H, d, J=12.6 Hz), 6.76 (1H, dd, J=7.8, 0.9 Hz),7.18 (1H, t, J=8.4 Hz), 7.23 (1H, t, J=1.5 Hz), 7.38-7.42 (2H, m), 7.57(1H, dd, J=8.4, 0.9 Hz), 7.77-7.82 (2H, m) 20-7 H SO₂Et H 153-155 1.23(3H, t, J=7.5), 2.41 (6H, s), 2.87- (dec.) 3.14 (3H, m), 3.28 (3H, q,J=7.5 Hz), oxalate 4.22 (1H, dd, J=12.3, 6.6 Hz), 4.49 (1H, d, J=12.3Hz), 6.82 (1H, d, J=7.8 Hz), 7.19-7.27 (2H, m), 7.50 (1H, J=8.4 Hz) 20-8H IPr H 191-194 1.49 (3H, t, J=6.3 Hz), 1.50 (3H, t, J= (dec.) 6.3 Hz),2.42 (6H, s), 2.93-3.24 (3H, m), oxalate 4.13 (1H, dd, J=12.3, 6.6 Hz),4.54 (1H, dd, J=12.3, 1.8 Hz), 4.57-4.66 (1H, m), 6.59 (1H, dd, J=7.8,1.2 Hz), 6.94 (1H, d, J=7.5 Hz), 7.01 (1H, s), 7.07 (1H, d, J= 7.8 Hz)20-9 H

H 142-144 (dec.) oxalate 2.37 (6H, s), 2.81-3.10 (3H, m), 4.16 (1H, dd,J=12.3, 6.6 Hz), 4.43 (1H, dd, J=12.3 Hz), 6.78 (1H, d, J=8.4 Hz), 7.00(1H, dd, J=4.8, 3.9 Hz), 7.21 (1H, t, J=8.4 Hz), 7.30 (1H, s), 7.53 (1H,dd, J=5.1, 1.5 Hz), 7.62 (1H, d, J=8.4 Hz), 7.67 (1H, dd, J=4.2, 1.5 Hz)20-10 H

H 119-122 (dec.) oxalate 2.37 (6H, s), 2.82-2.88 (1H, m), 2.96-3.11 (2H,m), 4.16 (1H, dd, J=12.6, 6.6 Hz), 4.43 (1H, d, J=12.6 Hz), 6.78 (1H,dd, J=8.1, 0.9 Hz), 7.17-7.32 (2H, m), 7.59 (1H, dd, J=8.1, 0.6 Hz),7.71 (2H, d, J=8.4 Hz), 8.00 (2H, d, J=8.1 Hz) 20-11 H

H 147-150 (dec.) oxalate 2.37 (6H, s), 2.82-3.12 (3H, m), 4.14 (1H, dd,J=12.6, 6.6 Hz), 4.43 (1H, d, J=12.6 Hz), 6.77 (1H, dd, J=7.8, 0.6 Hz),7.18 (1H, t, J=8.1 Hz), 7.30 (1H, s), 7.55-7.58 (2H, m), 7.71-7.74 (2H,m) 20-12 H

H 168-171 (dec.) oxalate 2.37 (6H, s), 2.81-3.11 (3H, m), 4.16 (1H, dd,J=12.3, 6.6 Hz), 4.42 (1H, d, J=12.3 Hz), 6.77 (1H, dd, J=8.1, 0.3 Hz),7.20 (1H, t, J=8.1 Hz), 7.30-7.34 (2H, m), 7.57 (1H, d, J=8.1 Hz),7.64-7.81 (2H, m), 8.01 (1H, t, J=1.8 Hz) 20-13 H

H 173-176 (dec.) oxalate 2.40 (6H, s), 2.86-3.11 (3H, m), 4.21 (1H, dd,J=12.3, 6.6 Hz), 4.60 (1H, d, J=12.3 Hz), 6.75 (1H, dd, J=8.1, 0.6 Hz),7.09 (1H, t, J=8.1 Hz), 7.23-7.26 (1H, m), 7.36-7.50 (2H, m), 7.55 (1H,s), 7.67 (1H, dd, J=7.8, 1.5 Hz), 8.09 (1H, dd, J=7.8, 1.5 Hz) 20-14 H

H 140-142 (dec.) oxalate 2.37 (6H, s), 2.81-3.11 (3H, m), 3.80 (3H, s),4.13 (1H, dd, J=12.3, 6.6 Hz), 4.43 (1H, d, J=12.3 Hz), 6.74 (1H, d,J=8.1 Hz), 6.88 (2H, dd, J=6.9, 2.1 Hz), 7.17 (1H, t, J=8.4 Hz), 7.33(1H, s), 7.58 (1H, d, J=8.1 Hz), 7.82 (1H, dd, J=6.9, 2.1 Hz) 20-15 H

H 123-126 (dec.) oxalate 2.37 (6H, s), 2.82-3.11 (3H, m), 3.85 (3H, s),3.87 (3H, s), 4.14 (1H, dd, J=12.3, 5.7 Hz), 4.44 (1H, d, J=12.3 Hz),6.75 (1H, dd, J=7.8, 0.9 Hz), 6.84 (2H, d, J=8.7 Hz), 7.17 (1H, t, J=8.1Hz), 7.26-7.32 (2H, m), 7.51 (1H, dd, J=8.4, 2.1 Hz), 7.61 (1H, dd,J=8.4, 0.6 Hz) 20-16 H

H 169-171 (dec.) oxalate 2.39 (6H, s), 2.85-3.13 (3H, m), 4.19 (1H, dd,J=12.6, 6.3 Hz), 4.46 (1H, d, J=12.6 Hz), 6.74 (1H, d, J=15.3 Hz), 6.80(1H, dd, J=8.4, 0.6 Hz), 7.20 (1H, t, J=8.4 Hz), 7.27-7.45 (6H, m), 7.52(1H, dd, J=8.1, 0.9 Hz), 7.70 (1H, d, J=15.5 Hz) 20-17 H

H 161-163 (dec.) oxalate 2.39 (6H, s), 2.84-3.09 (3H, m), 4.21 (1H, dd,J=12.3, 5.4 Hz), 4.44 (1H, d, J=12.3 Hz), 6.77 (1H, dd, J=8.4, 0.9 Hz),7.13 (1H, t, J=8.4 Hz), 7.25 (1H, dd, J=8.1, 0.9 Hz), 7.35 (1H, d, J=8.4Hz), 7.43-7.48 (2H, m), 8.19 (1H, d, J=2.4 Hz) 20-18 H SO₂Ph Br 89-902.39 (6H, s), 2.85-3.10 (3H, m), 4.24 (1H, dd, J=12.3, 6.3 Hz), 4.54(1H, d, J= 12.3 Hz), 7.34 (1H, s), 7.39-7.59 (5H, m), 7.84-7.87 (2H, m)20-19 H

H 143-144 (dec.) oxalate 2.37 (6H, s), 2.82-2.88 (1H, m), 2.96-3.11 (2H,m), 4.15 (1H, dd, J=12.6, 6.6 Hz), 4.42 (1H, d, J=12.6 Hz), 6.76 (1H, d,J=7.8 Hz), 7.08-7.21 (3H, m), 7.25 (1H, dd, J=8.1, 0.9 Hz), 7.31 (1H,s), 7.56 (1H, d, J=8.4 Hz), 7.87-7.92 (2H, m) 20-20 H

H 128-131 (dec.) oxalate 2.40 (6H, s), 2.85-2.91 (1H, m), 3.07-3.10 (2H,m), 4.21 (1H, dd, J=12.6, 6.6 Hz), 4.44 (1H, d, J=12.6 Hz), 6.79 (1H,dd, J=8.1, 0.9 Hz), 7.12 (1H, t, J=8.1 Hz), 7.33-7.42 (3H, m), 7.78 (1H,dd, J=7.2, 6.0 Hz) 20-21 H

H 154-154 (dec.) oxalate 2.38 (6H, s), 2.83-3.13 (3H, m), 4.18 (1H, dd,J=12.6, 6.6 Hz), 4.44 (1H, d, J=12.6 Hz), 6.80 (1H, dd, J=8.1, 0.6 Hz),6.83 (1H, d, J=4.2 Hz), 7.19-7.25 (2H, m), 7.46 (1H, d, J=4.1 Hz), 7.56(1H, dd, J=8.1, 0.6 Hz) 20-22 H

H 163-164 (dec.) oxalate 2.38 (6H, s), 2.82-3.09 (3H, m), 4.19 (1H, dd,J=12.3, 6.3 Hz), 4.44 (1H, d, J=12.3 Hz), 6.75-7.03 (3H, m), 7.13 (1H,t, J=8.1 Hz), 7.38-7.41 (2H, m), 8.02-8.11 (1H, m) 20-23 H

H 147-150 (dec.) oxalate 2.39 (6H, s), 2.84-3.10 (3H, m), 3.66 (3H, s),3.82 (3H, s), 4.18 (1H, dd, J=12.3, 6.6 Hz), 4.44 (1H, d, J=12.3 Hz),6.72 (1H, dd, J=8.1, 0.9 Hz), 6.81 (1H, d, J=9.0 Hz), 7.04 (1H, dd,J=9.0, 3.3 Hz), 7.09 (1H, t, J=8.1 Hz), 7.36 (1H, d, J=8.1 Hz), 7.43(1H, s), 7.60 (1H, d, J=3.3 Hz) 20-24 H

H 103-104 2.37 (6H, s), 2.82-3.12 (3H, m), 3.79 (3H, s), 3.82 (3H, s),4.15 (1H, dd, J=12.6, 6.6 Hz), 4.43 (1H, d, J=12.6 Hz), 6.75 (1H, dd,J=8.1, 0.6 Hz), 7.03-7.07 (1H, m), 7.17 (1H, t, J=8.1 Hz), 7.31-7.46(4H, m), 7.60 (1H, dd, J=8.1, 0.6 Hz) 20-25 H

H 113-115 (dec.) oxalate 2.32 (6H, s), 2.81-3.12 (3H, m), 4.17 (1H, dd,J=12.6, 6.3 Hz), 4.44 (1H, d, J=12.6 Hz), 6.46 (1H, d, J=1.8 Hz), 6.80(1H, d, J=7.8 Hz), 7.24 (1H, t, J=8.1 Hz), 7.29 (1H, d, J=3.9 Hz), 7.33(1H, d, J=3.9 Hz), 7.61 (1H, d, J=7.8 Hz), 7.64 (1H, d, J=3.9 Hz), 8.27(1H, d, J =1.8 Hz) 20-26(*) H SO₂Ph H 98-98 1.09 (3H, t, J=7.2 Hz), 2.34(3H, s), (dec.) 2.50-2.74 (2H, m), 2.91-3.16 (3H, m), oxalate 4.05 (1H,dd, J=12.0, 6.6 Hz), 4.51 (1H, dd, J=12.0, 0.9 Hz), 6.74 (1H, dd, J=8.1, 0.6 Hz), 7.17 (1H, t, J=8.1 Hz), 7.34 (1H, s), 7.41-7.61 (5H, m),7.86- 7.89 (2H, m) 20-27 Me SO₂Ph Me 155-158 2.24 (3H, s), 2.39 (6H, s),2.52 (3H, s), (dec.) 4.05 (1H, dd, J=12.6, 5.7 Hz), 4.46 (1H, oxalate d,J=12.6 Hz), 7.01 (1H, d, J=8.7 Hz), 7.38-7.43 (2H, m), 7.49-7.55 (1H,m), 7.71-7.77 (3H, m)

Method 2)(2-Benzenesulfonyl-2,7,8,9-tetrahydro-6-oxo-2-aza-benzo[cd]azulen-8-yl)dimethylamine(20-1)

[0175] n-BuLi (1.56 mol/l hexane solution) 1.39 ml was added to asolution of compound (19-1) 432 mg in dry tetrahydrofuran 10 ml at −70°C. under nitrogen atmosphere. The solution was stirred at thattemperature for 1 h and at −30° C. for 1 h. Then, the temperature wasagain lowered to −70° C. and benezenesulofonyl chloride 396 mg was addeddropwise. The reaction temperature was allowed to raise gradually to theroom temperature. The mixture was stirred at room temperature, poured toice and an aqueous ammonium chloride solution and extracted withchloroform. The chloroform layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue obtained was choromatographed on aluminum oxide 12 g inchloroform:hexane (8:1) to give the titled compound as crystals. Yield83%. The product was recrystallized from ethyl acetate isopropyl etherto give colorless crystals. m.p. 114-116° C.

[0176]¹H-NMR(CDCl₃): 2.36 (6H, s), 2.80-3.12 (3H, m), 4.13 (1H, dd,J=12.3, 6.6 Hz), 4.42 (1H, dd, J=12.3, 0.6 Hz), 6.75 (1H, d, J=8.1 Hz),7.14-7.20 (1H, m), 7.34 (1H, s), 7.41-7.61 (4H, m), 7.86-7.89 (2H, m)

EXAMPLE 14(1-Bromo-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine(21),(1,5-Dibromo-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethyl-amine(22) and(1,3-Dibromo-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethyl-amine(23)

[0177] N-Bromosuccinimide 214 mg was added to a warm solution ofcompound (19-1) 216 mg in carbon tetrachloride 33 ml and the mixture washeated under reflux for 2 h. After the reaction ceased, the insolublematerials were removed by filtration and washed with chloroform. Thefiltrate was concentrated under reduced pressure. The residue obtainedwas chromatographed on silica gel in chloroform:methanol (30:1). Theeluent was chromatographed on thin silica gel plates inchloroform:methanol (30:1) to give the titled compound (21) 51 mg. Yield17%. This was recrystallized from ethyl acetate-ether to give crystals,m.p. 170-172° C.

[0178]¹H-NMR(CDCl₃): 2.43 (6H, s), 2.88-3.08 (3H, m), 4.15 (1H, dd,J=12.3, 6.0 Hz), 4.52 (1H, d, J=12.3 Hz), 6.62 (1H, dd, J=7.8, 0.9 Hz),6.89 (1H, dd, J=8.1, 0.9 Hz), 7.04 (1H, t, J=7.8 Hz), 8.07 (1H, br s)

[0179] 1,5-Dibromo compound (22) 15 mg was isolated from anotherfraction. Yield 4% Purifying from ether gave crystals, m.p. 123-126° C.

[0180]¹H-NMR(CDCl₃): 2.44 (6H, s), 2.84-3.08 (3H, m), 4.21 (1H, dd,J=12.0, 6.9 Hz), 4.66 (1H, d, J=12.0 Hz), 6.78 (1H, d, J=8.7 Hz), 7.25(1H, d, J=8.7 Hz), 8.49 (1H, br s)

[0181] The mother liquor of the above mentioned 1,5-dibromo compound(22) was concentrated under reduced pressure and again chromatographedon thin silica gel plates in chloroform:methanol (30:1) to give the1,3-dibromo compound (23) 8 mg (yield 2%). This was treated with 1 eq.oxalic acid to give the salt, m.p. 147-152° C. (dec.).

[0182]¹H-NMR(CDCl₃): 2.42 (6H, s), 2.90-3.05 (3H, m), 4.09-4.16 (1H, m),4.50 (1H, d, J=12.0 Hz), 6.53 (1H, d, J=8.1 Hz), 7.15 (1H, d, J=8.1 Hz),8.22 (1H, br s)

EXAMPLE 152-Chloro-N-(2,7,8,9-tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)acetamide(24-1) (R═COCH₂Cl)

[0183] Compound (8-1) 535 mg was dissolved in dry tetrahydrofuran 15 ml.Triethylamine 345 mg and chloroacetyl chloride 0.25 ml were added to thesolution with cooling in ice. The mixture was stirred for 1 h and atroom temperature for 30 min. Ice-water was added to the mixture withcooling in ice. The mixture was extracted with ethyl acetate. Theextracts were washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue obtained waschromatographed on silica gel 25 g in ethyl acetate:hexane (2:1) to givethe titled compound 706 mg (94%) as a colorless oil.

[0184]¹H-NMR(CDCl₃): 3.06-3.14 (1H, m), 3.36-3.43 (1H, m), 3.95-4.06(2H, m), 4.08-4.16 (1H, m), 4.27 (1H, d, J=11.4 Hz), 4.54-4.64 (2H, m),6.70 (1H, dd, J=7.5, 1.2 Hz), 6.99 (1H, s), 7.03-7.13 (2H, m), 8.18 (1H,br s)

[0185] Following compounds were obtained, according to the similartreatment. Compd No R m.p. ¹H-NMR (CDCl₃) 24-2 COOMe Colorless 3.02-3.07(1H, m), 3.33-3.39 (1H, oil m), 3.63 (3H, s), 4.23 (1H, d, J=9.3 Hz),4.34-4.41 (1H, m), 4.53-4.60 (1H, m), 5.25 (1H, br d), 6.67 (1H, d,J=7.8 Hz), 6.97 (1H, s), 7.00-7.11 (2H, m), 8.14 (1H, br s) 24-3 MsColorless 3.02 (3H, s), 3.07-3-14 (1H, m), oil 3.35-3.42 (1H, m),4.19-4.27 (2H, m), 4.54-4.61 (1H, m), 4.84 (1H, d, J=8.7 Hz), 6.68 (1H,d, J=7.5 Hz), 7.00-7.12 (3H, m), 8.22 (1H, br s) 24-4 SO₂NHMe Yellow2.70 (3H, d, J=5.4 Hz), 3.04-3.11 oil (1H, m), 3.35-3.42 (1H, m), 4.03-4.28 (3H, m), 4.53-4.60 (1H, m), 4.81 (1H, d, J=8.4 Hz), 6.67 (1H, dd,J=7.2, 1.2 Hz), 6.98-7.11 (3H, m), 8.24 (1H, br s) 24-5 COMe 174-1761.92 (3H, s), 2.99-3.06 (1H, m), 3.35-3.41 (1H, m), 4.21-4.25 (1H, m),4.53-4.68 (2H, m), 6.03 (1H, br s), 6.69 (1H, d, J=7.2 Hz), 6.98 (1H,s), 7.03-7.13 (2H, m), 8.21 (1H, br s)

EXAMPLE 162-Cyclohexylamino-N-(2,7,8,9-tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)acetamide(25-1)

[0186] A solution of compound (24-1) 160 mg and cyclohexylamine 360 mgin benzene 4 ml and methanol 4 ml was heated at 60° C. for 21 h andconcentrated under reduced pressure. Water was added to the residueobtained. The mixture was extracted with chloroform. The extracts werewashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on silica gel in ethyl acetate:methanol (30:1) to givethe titled compound 161 mg as crystals. Yield 81%. The crude crystallinematerials were recrystallized from methanol-ethyl acetate to givecolorless crystals, m.p. 184-186° C.

[0187]¹H-NMR(CDCl₃): 0.43-1.04 (4H, m), 1.22-1.57 (6H, m), 1.98-2.07(1H, m), 3.02-3.46 (4H, m), 4.24-4.29 (1H, m), 4.54-4.59 (2H, m), 6.69(1H, dd, J=7.5, 0.9 Hz), 6.96-7.11 (3H, m), 7.96 (1H, br s), 8.13 (1H,br s)

[0188] Following compounds were obtained, according to the similartreatment. Compd No R m.p. ¹H-NMR (CDCl₃) 25-2 NMe₂ 161- 2.06 (6H, s),2.84-2.96 (2H, m), 3.06-3.13 162.5 (1H, m), 3.31-3.39 (1H, m), 4.26 (1H,d, J=11.4 Hz), 4.52-4.62 (2H, m), 6.68 (1H, dd, J=7.5, 0.9 Hz),6.97-7.11 (3H, m), 7.53 (1H, br s), 8.21 (1H, br s)

[0189] (Scheme of reactions, Examples 17-25)

EXAMPLE 17((R)-1-Phenylethyl)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine(26)

[0190] Sodium triacetoxyborohydride 318 mg and acetic acid 57 μl wereadded to a solution of compound (18-1) 187.6 mg and(R)-(+)-α-methylbenzylamine 13.7 mg in dry tetrahydrofuran 8 ml at roomtemperature and the mixture was stirred for 18 h. Water was added. Thereaction mixture was made alkaline with an aqueous saturated sodiumhydrogencarabonate solution and extracted with ether. The extracts werewashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on aluminum oxide 40 g in ethyl acetate:hexane (1:2) togive the titled compound 250 mg as a colorless oil. Yield 86%. The¹H-NMR shows the titled compound is a mixture of their diastereomers.

[0191]¹H-NMR(CDCl₃): 1.33 (total 6H, d, J=6.6 Hz), 2.98-3.22 (total 6H,m), 4.04-4.41 (total 6H, m), 6.61-6.65 (total 2H, m), 6.91-7.41 (total16H, m), 8.07 (total 2H, br s).

EXAMPLE 182,2,2-Trifluoro-N-((R)-1-phenylethyl)-N-(S)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylacetamide(27) and2,2,2-Trifluoro-N-((R)-1-phenylethyl)-N-(R)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylacetamide(28)

[0192] Compound (26) 2.548 g was dissolved in dry tetrahydrofuran 8 ml.A solution of triethylamine 1.34 ml and trifluoroacetic anhydride 2.014g in dry tetrahydrofuran 1 ml was added to the solution with cooling inice. The mixture was stirred for 1 h. Furthermore, triethylamine 177 mg,trifluoroacetic anhydride 366 mg were added and the mixture was stirredfor 1 h with cooling in ice. The solvents were removed by distillationunder reduced pressure. Water was added to the residue. The mixture wasextracted with ether. The extracts were washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue obtained was chromatographed on silica gel in ethylacetate:hexane (1:5) repeatedly to give the titled compound (27) as acolorless oil, 990 mg (yield 29%) and the titled compound (28) as acolorless oil 1.672 g (yield 49%).

[0193] Compound (27)

[0194]¹H-NMR(CDCl₃): 1.82 (3H, d, J=6.9 Hz), 2.07-2.19 (1H, m),3.54-3.66 (2H, m), 4.43 (1H, dd, J=12.9, 2.4 Hz), 4.81 (1H, dd, J=12.9,6.0 Hz), 5.40 (1H, q, J=6.9 Hz), 6.61 (1H, dd, J=7.5, 0.9 Hz), 6.64 (1H,m), 6.94 (1H, dd, J=7.5, 0.9 Hz), 7.04 (1H, t, J=7.5 Hz), 7.27-7.40 (5H,m), 7.96 (1H, br s).

[0195] Compound (28)

[0196]¹H-NMR(CDCl₃): 1.72 (3H, d, J=6.9 Hz), 3.00-3.08 (1H, m),3.55-3.63 (1H, m), 3.85-3.96 (1H, m), 4.10(1H, dd, J=12.6, 2.4Hz), 4.63(1H, dd, J=12.6, 6.3Hz), 5.39 (1H, q, J=6.9 Hz), 6.43 (1H, dd, J=7.5,1.2 Hz), 6.91-7.01 (3H, m), 7.34-7.44 (5H, m), 8.08 (1H, br s).

EXAMPLE 19((R)-1-Phenylethyl)-(S)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine(29)

[0197] Compound (27) 934 mg was dissolved in ethanol 19 ml and sodiumborohydride 364 mg was added to the solution at room temperature. Themixture was stirred for 17 h. Water was added with cooling in ice. Themixture was extracted with ethyl acetate. The extracts were washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue obtained was chromatographed on silica gelin ethyl acetate:hexane (1:1) to give the titled compound (29) 695 mg.Yield 99.9%. Furthermore, the titled compound (29) was treated with asolution of hydrogen chloride in methanol to give the HCl salt, whichwas recrystallized from methanol-isopropanol to give colorless crystals,m.p. 233-240° C. (dec.). The absolute configuration was determined by anX-ray crystal structure analysis on a single crystal.

[0198]¹H-NMR(CDCl₃): 1.33 (3H, d, J=6.3 Hz), 3.00-3.22 (3H, m), 4.03(1H, q, J=6.3 Hz), 4.21 (1H, d, J=11.7 Hz), 4.29-4.36 (1H, m), 6.63 (1H,dd, J=7.8, 0.9 Hz), 6.95-6.99 (2H, m), 7.06 (1H, t, J=7.8 Hz), 7.20-7.42(5H, m), 8.07 (1H, br s).

[0199] According to the similar manner,((R)-1-Phenylethyl)-(R)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine(30) was obtained.

[0200]¹H-NMR(CDCl₃): 1.33 (3H, d, J=6.6 Hz), 2.80-3.15 (3H, m), 4.11(1H, q, J=6.3 Hz), 4.26 (1H, d, J=12.0 Hz), 4.37 (1H, dd, J=12.0, 6.3Hz), 6.64 (1H, dd, J=7.8, 0.9 Hz), 6.91-6.93 (1H, m), 6.96 (1H, dd,J=7.8, 0.9 Hz), 7.06 (1H, t, J=7.8 Hz), 7.20-7.41 (5H, m), 8.06 (1H, brs).

EXAMPLE 20 (S)-2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine(31)

[0201] Compound (29) 609 mg was dissolved in tetrahydrofuran 20 ml. 20%Palladium(II)hydroxide 200 mg was added. A mixture was stirred in ahydrogen atomosphere for 22 h. The catalyst was filtered off and thefiltrate was concentrated under reduced pressure. The residue obtainedwas chromatographed on aluminum oxide in chloroform to give the titledcompound (31) as pale brown crystals, 337 mg. Yield 86%. Furthermore,this was recrystallized from methanol-isopropanol to give the titledcompound (31) as pale brown crystals, m.p. 202-203° C.

[0202] [α]_(D)+38.7±1.6° (C=0.509, methanol, 25° C.)

[0203] According to the similar manner,(R)-2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine (32) wasobtained.

[0204] m.p. 202-203° C. [α]_(D)−38.8±1.6° (C=0.508, methanol, 25° C.)

EXAMPLE 21 2,9-Dihydro-6-oxa-2-azabenzo[cd]azulen-8-one Ethylene Ketal(33)

[0205] Ethylene glycol 2.56 g and pyridinium p-toluenesulfonate 250 mgwere added to a solution of compound (18-1) 1.877 g in benzene 50 ml.The mixture was heated under reflux for 14 h by use of a Dean-Starkapparatus. The reaction mixture separated into two layers. The upperlayer was separated by decantation. Water and dioxane were added to theremained black oily part. The insoluble materials were removed byfiltration and the filtrate was extracted with toluene. The extractswere washed with brine, treated with char coal, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to give browncrystals. The above obtaied upper layer was washed with water, anaqueous saturated sodium hydrogen carbonate solution and brinesuccessively, treated with char-coal and dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give colorlesscrystals. The combined crystals were recrystallized from tetrahydrofuranto give the titled compound (33) as colorless crystals, m.p. 200-202°C., 925 mg. Yield 40%.

[0206]¹H-NMR(DMSO-d₆): 3.16 (2H, s), 3.97 (4H, s), 4.13 (2H, s), 6.41(1H, dd, J=6.6, 1.8 Hz), 6.88-6.96 (2H, m), 7.07 (1H, m), 10.94 (1H, brs).

EXAMPLE 222-Benzenesulfonyl-2,9-dihydro-6-oxa-2-azabenzo[cd]azulen-8-one EthyleneKetal (34)

[0207] 60% Sodium hydride 33 mg was added to a solution of compound (33)in dry dimethylformamide 2 ml with cooling in ice and the mixture wasstirred for 10 min. Then, benzenesulfonyl chloride 152 mg was added. Themixture was heated at 60° C. for 14 h. Ice-water was added to thereaction mixtures, which was extracted with ethyl acetate. The extractswere washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschoromatographed on aluminum oxide in chloroform:hexane (1:1) to givethe titled compound (34) as a pale yellow oil, 187 mg. Yield 69%.

[0208]¹H-NMR(CDCl₃): 3.22 (2H, s), 4.07 (4H, s), 4.16 (2H, s), 6.80 (1H,dd, J=8.1, 0.9 Hz), 7.18 (1H, t, J=8.1 Hz), 7.33 (1H, m), 7.42-7.58 (3H,m), 7.62 (1H, dd, J=8.4, 0.9 Hz), 7.88-7.92 (2H, m).

EXAMPLE 232-Benzenesulfonyl-2,9-dihydro-6-oxa-2-azabenzo[cd]azulen-8-one (35)

[0209] Trifluoroacetic acid 1 ml and water 0.1 ml were added to compound(34) 48.4 mg. The mixture was heated at 80° C. for 15 min andconcentrated under reduced pressure. Ice-water was added to the residue,which was made alkaline with an aqueous saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The extracts werewashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on silica gel in ethyl acetate:hexane (1:2) to give thetitled compound (35) as a colorless oil, 33.2 mg. Yield 78%.

[0210]¹H-NMR(CDCl₃): 4.03 (2H, d, J=1.2 Hz), 4.62 (2H, s), 6.90 (1H, dd,J=7.8, 0.6 Hz), 7.25 (1H, t, J=7.8 Hz), 7.30 (1H, m), 7.44-7.61 (3H, m),7.73 (1H, dd, J=7.8, 0.6 Hz), 7.88-7.93 (2H, m).

EXAMPLE 242-Benzenesulfonyl-8-pyrrolidin-1-yl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulene(36-1) (R⁴=pyrrolidinyl)

[0211] A solution of pyrrolidine 35.4 mg in dry tetrahydrofuran 0.5 ml,sodium triacetoxyborohydride 133.7 mg and acetic acid 26 μl were addedto a solution of compound (35) 135.9 mg in dry tetrahydrofuran 3.5 ml atroom temperature and the mixture was stirred for 24 h. Water was addedto the reaction mixture, which was made alkaline with an aqueoussaturated sodium hydrogencarbonate solution and extracted with ethylacetate. The extracts were washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueobtained was chromatographed on aluminum oxide 20 g in chloroform togive the titled compound (36-1) as a brown oil, 97.7 mg. Yield 62%. Thiswas treated with 1 eq. oxalic acid to give the salt which wasrecrystallized from ether-methanol to give colorless crystals, m.p.170-173° C.(dec.).

[0212]¹H-NMR(CDCl₃): 1.76-1.84 (4H, m), 2.60-3.26 (7H, m), 4.12 (1H, dd,J=12.9, 6.3 Hz), 4.47 (1H, d, J=12.9 Hz), 6.73 (1H, dd, J=8.1, 0.9 Hz),7.17 (1H, t, J=8.1 Hz), 7.33 (1H, s), 7.41-7.61 (4H, m), 7.86-7.90 (2H,m).

[0213] Following compounds were obtained, according to the similartreatment. Compd m.p. No R⁷ (° C.) ¹H-NMR (CDCl₃) 36-2 NHMe 208-213 2.52(3H, s), 2.91-3.15 (3H, m), (dec.) 4.22-4.27 (2H, m), 6.76 (1H, dd,J=8.1, oxalate 0.9 Hz), 7.18 (1H, t, J=8.1 Hz), 7.32-7.34 (1H, m),7.41-7.58 (3H, m), 7.61 (1H, dd, J=8.1, 0.9 Hz), 7.86-7.90 (2H, m) 36-3NEt₂ 106-108 1.07 (6H, t, J=6.9 Hz), 2.50-3-30 (7H, m), 3.98-4.05 (1H,m), 4.52 (1H, d, J=11.7 Hz), 6.74 (1H, dd, J=7.8, 0.9 Hz), 7.17 (1H, t,J=7.8 Hz), 7.33 (1H, s), 7.42-7.62 (4H, m), 7.86-7.90 (2H, m) 36-4 NHBn208-209 2.94-3.11 (2H, m), 3.20-3.27 (1H, m), (dec.) 3.86 (1H, d, J=13.2Hz), 3.95 (1H, d, oxalate J=13.2 Hz), 4.27 (2H, d, J=3.9 Hz), 6.77 (1H,d, J=7.8 Hz), 7.15-7.62 (11H, m), 7.86-7.90 (2H, m)

EXAMPLE 25 2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ol(37)

[0214] Compound (18-1) 374.4 mg was suspended in methanol 5 ml andsodium borohydride 75.7 mg was added to the suspension with cooling inice. The mixture was stirred for 1 h. Water was added with cooling inice. The mixture was extracted with ethyl acetate. The extracts werewashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained wasrecrystallized from acetone-isopropanol to give the titled compound (37)as colorless crystals m.p. 169-170° C., 356.5 mg. Yield 94%.

[0215]¹H-NMR(CD₃OD): 2.83-2.93 (1H, m), 3.29-3.38 (1H, m), 4.03-4.17(2H, m), 4.32 (1H, dd, J=5.4, 2.1 Hz), 6.42-6.48 (1H, m), 6.88-6.95 (1H,m), 6.99 (1H, br s).

[0216] (Scheme of reactions, Examples 26-34)

EXAMPLE 26Dimethyl-(5-phenyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)amine(38)

[0217] Phenylboronic acid 190.1 mg, palladium acetate 13.0 mg,tris(2-methylphenyl)phosphine 30.9 mg and potassium carbonate 691.0 mgwere added to a solution of compound (19-16) 296 mg in drydimethylformamide 6 ml under nitrogen atmosphere. The mixture was heatedat 120° C. for 2 h. After cooling, water was added. The mixture wasextracted with ethyl acetate. The extracts were washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue obtained was chromatographed on aluminum oxide inethyl acetate:toluene (1:2) to give the titled compound (38) ascolorless crystals, 33.0 mg. Yield 11%. Furthermore, the titled compoundwas recrystallized from acetone-isopropyl ether to give colorlesscrystals, m.p. 168-170° C.

[0218]¹H-NMR(CDCl₃): 2.42 (6H, s), 2.96-3.28 (3H, m), 4.17 (1H, dd,J=12.3, 6.3 Hz), 4.53 (1H, d, J=12.3 Hz), 7.02 (1H, s), 7.03 (1H, d,J=8.4 Hz), 7.15 (1H, d, J=8.4 Hz), 7.27-7.60 (5H, m).

EXAMPLE 27(E)-3-(8-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-5-yl)acrylicAcid Methyl Ester (39)

[0219] Methyl acrylate 140 μl, triethylamine 217 μl andbis(triphenylphosphine)palladium dichloride 0.2 mg were added to asolution of compound (19-16) 306 mg in dry dimethylformamide 5 ml undernitrogen atmosphere. The mixture was heated at 100° C. for 19 h. Waterwas added with cooling in ice. The mixture was extracted with ethylacetate. The extracts were washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueobtained was chromatographed on aluminum oxide in ethyl acetate:hexane(1:1) to give the titled compound as yellow crystals 146.5 mg. Yield47%. The titled compound was recrystallized from acetone-isopropyl etherto give pale yellow crystals, m.p. 168-170° C.

[0220]¹H-NMR(CDCl₃): 2.43 (6H, s), 2.90-3.22 (3H, m), 3.80 (3H, s), 4.24(1H, dd, J=12.0, 6.6 Hz), 4.63 (1H, dd, J=12.6, 0.9 Hz), 6.39 (1H, d,J=16.2 Hz), 6.94 (1H, d, J=8.7 Hz), 6.97 (1H, m), 7.34 (1H, d, J=8.7Hz), 8.22 (1H, br s), 8.25 (1H, d, J=16.2 Hz).

EXAMPLE 28Dimethyl-(5-vinyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)amine(40)

[0221] Tri-n-butylvinyltin 952.0 mg, tetrakistriphenylphosphinepalladium116.1 mg and lithium chloride 254.0 mg were added to a solution ofcompound (19-16) 592.2 mg in dry dimethylformamide 30 ml under anitrogen atmosphere. The mixture was heated at 120° C. for 4 h anddiluted with ethyl acetate, after cooling. The insoluble materials wereremoved by filtration through cerite. The filtrate was washed with anaqueous saturated sodium hydrogencarbonate solution and brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue obtained was chromatographed on aluminum oxide inethyl acetate:toluene (1:2) to give a colorless oil 602.2 mg. This waschromatographed on silica gel in chloroform:methanol:aq. ammonia(46:10:1) to give a yellow oil 500 mg, which was crystallized fromhexane giving the titled compound as colorless crystals, 324 mg. Yield67%. Furthermore, the titled compound was recrystallized fromether-petroleumether to give colorless crystals, m.p.119-120° C.

[0222]¹H-NMR(CDCl₃): 2.43 (6H, s), 2.93-3.23 (3H, m), 4.12-4.19 (1H, m),4.61 (1H, dd, J=12.6, 1.5 Hz), 5.13 (1H, dd, J=11.4, 1.5 Hz), 5.62 (1H,dd, J=18.0, 1.5 Hz), 6.91-6.96 (2H, m), 7.22 (1H, dd, J=18.0, 11.4 Hz),7.34 (1H, d, J=8.4 Hz), 8.08 (1H, br s).

EXAMPLE 29(5-Ethyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd](azulen-8-yl)dimethylamine(41)

[0223] Compound (40) 242 mg was dissolved in methanol 4 ml and 5%palladium/C 60 mg was added. A mixture was stirred in hydrogenatmosphere at room temperature for 3 h. The catalyst was filtered offand the filtrate was concentrated under reduced pressure. The residueobtained was chromatographed on aluminum oxide in ethyl acetate:hexane(1:2) to give the titled compound as colorless crystals 241.6 mg. Yield99%. This was recrystallized from acetone-hexane to give the titledcompound as colorless crystals, m.p. 91-92° C.

[0224]¹H-NMR(CDCl₃): 1.21 (3H, t, J=7.5 Hz), 2.44 (6H, s), 2.65-2.78(2H, m), 2.94-3.23 (3H, m), 4.12-4.18 (1H, m), 4.54-4.59 (1H, m), 6.90(1H, d, J=8.4 Hz), 6.94-6.96 (1H, m), 6.97 (1H, d, J=8.4 Hz), 7.96 (1H,br s).

EXAMPLE 30(5-Bromo-2-triisopropylsilanyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine(42)

[0225] Compound (19-16) 2.00 g was added to a suspension of 60% sodiumhydride 300.8 mg in tetrahydrofuran 30 ml with cooling in ice. Themixture was stirred for 1 h. Then, triisopropylsilyl chloride (TIPSCl)1.6 ml was added with cooling in ice. The mixture was stirred for 4 hwith cooling in ice. Water was added to reaction mixture with cooling inice. The mixture was extracted with ethyl acetate. The extracts werewashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on aluminum oxide in ethyl acetate:hexane (1:4) to givea pale brown oil 2.67 g. This was recrystallized from isopropyl ether togive colorless crystals, m.p. 119-121° C. 1.85 g. Yield 60%.

[0226]¹H-NMR(CDCl₃): 1.13 (18H, dd, J=7.5, 0.9 Hz), 1.58-1.72 (3H, m),2.45 (6H, s), 3.03-3.26 (3H, m), 4.18-4.24 (1H, m), 4.66 (1H, dd,J=12.3, 1.5 Hz), 6.96 (1H, d, J=8.7 Hz), 7.00 (1H, s), 7.20 (1H, d,J=8.7 Hz).

EXAMPLE 31(5-Fluoro-2-triisopropylsilanyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine(43)

[0227] A solution of compound (42) 451 mg in dry tetrahydrofuran 5 mlwas cooled at −70° C. n-BuLi (1.56 mol/l hexane solution) 1.3 ml wasadded dropwise to the mixture, which was stirred for 1 h. Then,N-fluorobenzenesulfonimide 694 mg was added and the mixture was stirredfor 3.5 h. The reaction mixtures was diluted with an aqueous ammoniumchloride solution, extracted with ethyl acetate. The extracts werewashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on aluminum oxide in ethyl acetate:hexane (1:5) to givea yellow oil. This was chromatographed on thin aluminum oxide plates(Merck precoated TLC plate alumina 60F254 in ethyl acetate:hexane (1:5))to give the titled compound as a pale yellow oil, 100 mg.

[0228]¹H-NMR(CDCl₃): 1.28 (18H, dd, J=7.5, 0.9 Hz), 1.58-1.70 (3H, m),2.45 (6H, s), 2.95-3.28 (3H, m), 4.20-4.26 (1H, m), 4.62 (1H, dd,J=11.7, 1.2 Hz), 6.86-6.97 (2H, m), 7.03 (1H, s).

EXAMPLE 32Dimethyl-(5-methylsulfanyl-2-triisopropylsilanyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulen-8-yl)amine(44)

[0229] A solution of compound (42) 451 mg in dry tetrahydrofuran 5 mlwas cooled at −70° C. n-BuLi (1.56 mol/l hexane solution) 1.3 ml wasadded dropwise to the solution and the mixture was stirred for 1 h.Then, dimethyldisulfide 185 μl was added and the mixture was stirred for2 h. The reaction mixtures was diluted with an aqueous ammonium chloridesolution and extracted with ethyl acetate. The extracts were washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue obtained was chromatographed on aluminumoxide in ethyl acetate:hexane (1:5) to give the titled compound ascolorless crystals, 289.8 mg. Yield 69%. This was recrystallized fromhexane to give the titled compound as colorless crystals, m.p. 77-79° C.

[0230]¹H-NMR(CDCl₃): 1.13 (18H, d, J=7.5 Hz), 1.58-1.74 (3H, m), 2.45(total 9H, each s), 2.97-3.30 (3H, m), 4.22 (1H, d, J=12.0, 6.3 Hz),4.68 (1H, dd, J 12.0, 1.2 Hz), 6.99 (1H, s), 7.04 (1H, d, J=8.4 Hz),7.10 (1H, d, J=8.7 Hz).

EXAMPLE 338-Dimethylamino-2-triisopropylsilanyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulene-5-carbaldehyde(45)

[0231] A solution of compound (42) 750 mg in dry tetrahydrofuran 7 mlwas cooled at −70° C. and n-BuLi (1.56 mol/l hexane solution) 2.2 ml wasadded dropwise to the solution. The mixture was stirred for 1 h.Dimethylformamide 257 μl was added and the mixture was stirred for 2 h.The reaction mixtures was diluted with an aqueous ammonium chloridesolution and extracted with ethyl acetate. The extracts were washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue obtained was chromatographed on aluminumoxide in ethyl acetate:hexane (1:4) to give the titled compound asyellow oil, 556 mg. This was recrystallized from hexane to give thetitled compound as colorless crystals, m.p. 104-106° C., 395 mg. Yield59%

[0232]¹H-NMR(CDCl₃): 1.14 (18H, d, J=7.5 Hz), 1.55-1.72 (3H, m), 2.45(6H, s), 2.97-3.30 (3H, m), 4.29 (1H, dd, J=12.6, 6.3 Hz), 4.65 (1H, d,J=12.6 Hz), 7.04 (1H, s), 7.07 (1H, d, J=9.0 Hz), 7.60 (1H, d, J=8.7Hz), 10.50 (1H, s).

EXAMPLE 348-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulene-5-carbaldehyde(46-1) (R₁₁═CHO)

[0233] Tetra-n-butylammoniumfluoride (1 mol/l tetrahydrofuran solution)2.2 ml was added to compound (45) 496 mg in tetrahydrofuran 10 ml withcooling in ice. The mixture was stirred for 3 h, diluted with water andethyl acetate and, extracted with ethyl acetate. The extracts werewashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on aluminum oxide in ethyl acetate:hexane (2:1) to givecolorless crystals, 273.2 mg. This was recrystallized fromacetone-isopropyl ether to give the titled compound as colorlesscrystals, m.p.175-176° C., 2654 m g. Yield 88%.

[0234]¹H-NMR(DMSO-d₆): 2.29 (6H, s), 2.78-3.13 (3H, m), 4.31 (1H, dd,J=12.3, 6.6 Hz), 4.58 (1H, d, J=12.3 Hz), 6.99 (1H, dd, J=8.4, 0.9 Hz),7.23 (1H, s), 7.40 (1H, d, J=8.4 Hz), 10.36 (1H, d, J=0.9 Hz), 11.48(1H, br s).

[0235] Following compounds were obtained, according to the similartreatment. Compd m.p. No R¹¹ (° C.) ¹H-NMR (CDCl₃) 46-2 F 148-150 2.44(6H, s), 2.93-3.25 (3H, m), 4.24 (1H, dd, J=12.3, 6.6 Hz), 4.63 (1H, dd,J=12.3, 1.2 Hz), 6.83 (1H, dd, J=8.7, 3.6 Hz), 6.97 (1H, dd, J=11.4, 8.7Hz), 7.01 (1H, m), 8.04 (1H, br s) 46-3 SMe 112-113 2.44 (3H, s), 2.44(6H, s), 2.97-3.24 (3H, m), 4.24 (1H, dd, J=12.3, 6.3 Hz), 4.69 (1H, dd,J=12.3, 2.1 Hz), 6.94 (1H, d, J=8.4 Hz), 6.97-6.99 (1H, m), 7.19 (1H, d,J=8.7 Hz), 8.09 (1H, br s)

[0236] (Scheme of reactions, Examples 35-37)

EXAMPLE 358-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulene-5-carbaldehydeOxime (47)

[0237] Hydroxylamine hydrogenchloride 83.4 mg and sodium acetate 98.4 mgwere added to a suspension of compound (46-1) 244 mg in 95% ethanol 10ml. The mixture was stirred at room temperature for 2 h and concentratedunder reduced pressure. Water was added to the residue, which was madealkaline with an aqueous saturated sodium hydrogencarbonate solution.Colorless precipitates appeared and were collected by filtration, washedwith methanol-ethyl acetate to give the titled compound as colorlesscrystals, m.p. 230-235° C.(dec.), 228 mg. Yield 88%.

[0238]¹H-NMR(DMSO-d₆): 2.28 (6H, s), 2.73-3.12 (3H, m), 4.15 (1H, dd,J=12.0, 6.6 Hz), 4.49 (1H, d, J=12.3 Hz), 6.93 (1H, d, J=7.8 Hz), 7.13(1H, br d, J=2.7 Hz), 7.38 (1H, d, J=8.7 Hz), 8.39 (1H, s), 10.66 (1H,s), 11.12 (1H, br s).

EXAMPLE 368-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulene-5-carbonitrile(48)

[0239] Triethylamine 33 μl and trichloroacetyl chloride 13 μl were addedto a solution of compound (47) 28.9 mg in dichloromethane 2 ml withcooling ice and the mixture was stirred with cooling in ice and at roomtemperature for 18 h. A saturated sodium hydrogencarbonate solution wasadded thereto for alkalinization. The mixture was extracted withchloroform. The extracts were washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueobtained was chromatographed on aluminum oxide in chloroform:methanol(97:3) to give the titled compound 26.3 mg as colorless crystals. Yield98%. Furthermore, the titled compound was recrystallized frommethanol-isopropyl ether to give colorless crystals, m.p. 205-207° C.

[0240]¹H-NMR(CD₃OD): 2.41 (6H, s), 2.89-3.23 (3H, m), 4.39 (1H, dd,J=12.6, 6.9 Hz), 4.64 (1H, d, J=12.6 Hz), 7.03 (1H, d, J=8.7 Hz), 7.17(1H, d, J=8.7 Hz), 7.18 (1H, m).

EXAMPLE 37 8-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulene-5-carboxylic Acid Amide (49)

[0241] Polyphophoric acid 420 mg was added to compound (48) 31.6 mgunder an argon atmosphere and the mixture was heated at 90° C. for 6 h.Ice-water was added to the reaction mixture, which was made alkalinewith an aqueous 5 N-sodium hydroxide solution and extracted withchloroform. The extracts were washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueobtained was chromatographed on aluminum oxide in chloroform:methanol(97:3) to give the titled compound as colorless crystals, 20.9 mg. Yield62%. Furthermore, the titled compound was recrystallized fromacetone-isopropyl ether to give colorless crystals, m.p. 182-183° C.

[0242]¹H-NMR(DMSO-d₆): 2.29 (6H, s), 2.76-3.13 (3H, m), 4.24 (1H, dd,J=12.0, 6.0 Hz), 4.64 (1H, d, J=12.3 Hz), 6.97 (1H, d, J=8.7 Hz), 7.18(1H, d, J=2.1 Hz), 7.22 (1H, br s), 7.66 (1H, d, J=8.7Hz), 7.68(1H, brs), 11.20 (1H, br s)

[0243] (Scheme of reactions, Examples 38-40)

EXAMPLE 38N-Cyclopropyl-2,2,2-trifluoromethyl-N-(2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)acetamide(50)

[0244] Compound (19-19) 355 mg was dissolved in dry tetrahydrofuran 11ml. A solution of triethylamine 178 mg and trifluoroacetic anhydride 344mg in dry tetrahydrofuran 0.5 ml was added to the solution with coolingin ice. The mixture was stirred with cooling in ice for 2 h.Triethylamine 78 mg and trifluoroacetic anhydride 156 mg in drytetrahydrofuran 0.2 ml were again added. The mixture was stirred withcooling in ice for 2 h and concentrated under reduced pressure. Waterwas added to the residue, which was extracted with ether. The extractswere washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on aluminum oxide 15 g in chloroform:hexane (4:1) togive the titled compound as pale yellow crystals, 415 mg (yield 82%),m.p. 49-53° C.

[0245]¹H-NMR(CDCl₃): 0.94-1.06 (4H, m), 3.04-3.14 (2H, m), 3.64-3.74(1H, m), 4.10-4.15 (1H, m), 4.46 (1H, dd, J=12.6, 1.8 Hz), 4.70 (1H, dd,J=12.6, 6.6 Hz), 6.64 (1H, dd, J=7.5, 1.2 Hz), 6.97 (1H, s), 7.00 (1H,dd, J=8.1, 1.2 Hz), 7.08 (1H, d, J=8.1 Hz), 8.17 (1H, br s)

EXAMPLE 39N-(2-Benzenesulfonyl-2,7,8,9-tetrahydro-6-oxo-2-aza-benzo[cd]azulen-8-yl)-N-cyclopropyl-2,2,2,-trifluoroacetamide(51)

[0246] 60% Sodium hydride 56 mg was added to a solution of compound (50)324 mg in dimethylformamide 12 ml with cooling in ice and the mixturewas stirred at room for 1 h. Benzenesulfonyl chloride 238 mg was addeddropwise with cooling in ice and then, the mixture was stirred at 40° C.for 21 h. Ice-water and then an aqueous sodium hydrogencarbonatesolution were added to the reaction mixture, which was extracted withethyl acetate. The extracts were washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueobtained was chromatographed on aluminum oxide in chloroform:hexane(1:2) to give the titled compound as a colorless oil, 130 mg (yield28%).

[0247]¹H-NMR(CDCl₃): 0.88-1.05 (4H, m), 3.03-3.09 (2H, m), 3.58-3.68(1H, m), 3.99-4.06 (1H, m), 4.40 (1H, dd, J=12.9, 1.5 Hz), 4.59 (1H, dd,J=12.9, 6.3 Hz), 6.77 (1H, dd, J=7.8, 0.6 Hz), 7.20 (1H, t, J=8.1 Hz),7.34 (1H, s), 7.44-7.66 (4H, m), 7.86-7.90 (2H, m)

EXAMPLE 40(2-Benzenesulfonyl-2,7,8,9-tetrahydro-6-oxo-2-aza-benzo[cd]azulen-8-yl)cyclopropylamine(52)

[0248] Compound (51) 129 mg was dissolved in ethanol 3 ml. Sodiumhydrogenborohydride 42 mg was added to the solution at room temperatureand the mixture was stirred for 23 h. Water was added with cooling inice to the reaction mixture, which was extracted with chloroform. Theextracts were washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue obtained waschromatographed on aluminum oxide in chloroform:hexane (1:1) to give thetitled compound as a colorless oil, 98 mg. Yield 96%. The titledcompound was treated with 1 eq. of oxalic acid to give the salt, whichwas recrystallized from isopropanol-ether to give colorless crystals,m.p. 119-122° C. (dec.).

[0249]¹H-NMR(CDCl₃): 0.30-0.49 (4H, m), 2.21-2.27 (1H, m), 2.94-3.12(2H, m), 3.31-3.37 (1H, m), 4.29-4.31 (2H, m), 6.77 (1H, d, J=7.8 Hz),7.19 (1H, t, J=8.1 Hz), 7.33 (1H, s), 7.42-7.63 (4H, m), 7.86-7.90 (2H,m)

[0250] (Scheme of reactions, Examples 41-44)

EXAMPLE 41(2-Benzenesulfonyl-1-iodo-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine(53)

[0251] LDA was prepared by addition of n-BuLi (1.56 mol/l hexanesolution) 1.08 ml to a solution of diisopropylamine 255 μl in drytetrahydrofuran 3 ml at −70° C. Then, a solution of compound (20-1) 500mg in dry tetrahydrofuran 2 ml was added at that temperature to themixture, which was stirred for 2 h. Then, a solution of iodine 426 mg indry tetrahydrofuran 2 ml was added and the mixture was stirred for 2 h.Ice was added to the reaction mixtures, which was extracted withchloroform. The extracts were washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueobtained was chromatographed on aluminum oxide in ethyl acetate:hexane(1:5) to give the titled compound as colorless crystals 514 mg. Yield76%. This was recrystallized from from acetone-isopropyl ether to givecolorless crystals, m.p. 136-137° C.

[0252]¹H-NMR(CDCl₃): 2.36 (6H, s), 2.87-2.97 (3H, m), 4.08-4.14 (1H, m),4.41 (1H, d, J=12.6 Hz), 6.75 (1H, d, J=7.5 Hz), 7.40-7.45 (2H, m),7.53-7.58 (1H, m), 7.86-7.90 (2H, m), 7.96 (1H, d, J=7.8 Hz).

EXAMPLE 42(2-Benzenesulfonyl-1-vinyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine(54)

[0253] Tri-n-butyl(vinyl)tin 484.4 mg,tetrakis(triphenylphosphine)palladium 690 mg and lithium chloride 127.7mg were added to a solution of compound (53) 491 mg in drydimethylformamide 10 ml under nitrogen atmosphere. The mixture washeated at 100° C. for 3 h, diluted with ethyl acetate after cooling andfiltered through cerite to remove the insoluble materials. The filtratewas washed with an aqueous saturated sodium hydrogencarbonate solutionand brine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue obtained was pulverized in hexane,collected by filtration and chromatographed on aluminum oxide inchloroform:hexane (1:1) to give the titled compound as colorlesscrystals 602.2 mg. Yield 79%. Furthermore, the titled compound wasrecrystallized from acetone-isopropyl ether to give colorless crystals,m.p. 133-134° C.

[0254]¹H-NMR(CDCl₃): 2.53 (6H, s), 2.78-3.10 (3H, m), 4.11 (1H, dd,J=12.6, 6.6 Hz), 4.41 (1H, d, J=12.6 Hz), 5.36 (1H, dd, J=17.7, 1.5 Hz),5.69 (1H, dd, J=11.4, 1.5 Hz), 6.77 (1H, dd, J=8.1, 0.9 Hz), 7.18 (1H,dd, J=18.0, 11.4 Hz), 7.19 (1H, t, J=8.1 Hz), 7.34-7.53 (3H, m),7.73-7.76 (2H, m), 7.87 (1H, dd, J=8.4, 0.9 Hz).

EXAMPLE 43(2-Benzenesulfonyl-1-ethyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine(55)

[0255] Compound (54) 200.1 mg was dissolved in a mixture of methanol 8ml and tetrahydrofuran 4 ml. 10% Pd/C 49.8 mg was added. The mixture wasstirred under hydrogen atmosphere for 18 h at room temperature. Thecatalyst was filtered off and the filtrate was concentrated underreduced pressure. The residue obtained was chromatographed on aluminumoxide in chloroform:hexane (1:1) to give the titled compound as acolorless oil 198 mg. Yield 98%. This was treated with 1 eq. of oxalicacid to give the salt, which was recrystallized from ether-methanol togive colorless crystals, m.p. 193-194° C.(dec.).

[0256]¹H-NMR(CDCl₃): 1.28 (3H, t, J=7.5 Hz), 2.41 (6H, s), 2.89-3.07(5H, m), 4.07-4.13 (1H, m), 4.43 (1H, d, J=12.6 Hz), 6.75 (1H, dd,J=7.8, 0.9 Hz), 7.13 (1H, t, J=8.1 Hz), 7.37-7.43 (2H, m), 7.49-7.54(1H, m), 7.71-7.75 (2H, m), 7.83 (1H, dd, J=8.1, 0.9 Hz).

EXAMPLE 44(1-Ethyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine(56-1)

[0257] Magnesium (turning) 246 mg was added to compound (55) in methanol9 ml and the mixture was stirred at room temperature for 3 h. Ice wasadded to the reaction mixture which was diluted with chloroform. Theinsoluble materials were filtered off through cerite and the filtratewas extracted with chloroform. The extracts were washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue obtained was chromatographed on aluminum oxide inchloroform:hexane (2:1) to give the titled compound as a pale yellow oil97.8 mg. Yield 79%. This was treated with 1 eq. oxalic acid to give thesalt, which was recrystallized from ether-methanol to give colorlesscrystals, m.p. 236-237° C. (dec.).

[0258]¹H-NMR(CDCl₃): 1.29 (3H, t, J=7.5 Hz), 2.45 (6H, s), 2.75 (2H, q,J=7.5 Hz), 2.86-3.13 (3H, m), 4.12 (1H, dd, J=12.3, 6.3 Hz), 4.54 (1H,d, J=12.3 Hz), 6.59 (1H, dd, J=7.5, 0.9 Hz), 6.91 (1H, dd, J=8.1, 0.9Hz), 6.99 (1H, t, J=7.8 Hz), 7.90 (1H, br s).

[0259] Following compounds were obtained, according to the similartreatment. Compd No R⁷ m.p. ¹H-NMR (CDCl₃) 56-2 vinyl 195-198 2.43 (6H,s), 2.64-3.25 (3H, m), 4.12 (dec.) (1H, dd, J=12.0, 6.3 Hz), 4.54 (1H,oxalate dd, J=12.0, 2.1 Hz), 5.27 (1H, d, J=11.4 Hz), 5.43 (1H, d,J=11.4 Hz), 6.58 (1H, dd, J=7.8, 0.9 Hz), 6.79 (1H, dd, J=17.7, 11.4Hz), 6.91 (1H, dd, J=8.1, 0.9 Hz), 7.06 (1H, t, J=8.1 Hz), 8.11 (1H, brs),

EXAMPLE 45

[0260]

N-(2,7,8,9-Tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)hydrazinecarboxylicAcid tert-butyl Ester (57)

[0261] t-Butylbuthoxycarbonyl hydrazide 139 mg was added to a solutionof compound (18-1) 170 mg in dry tetrahydrofuran 6 ml. The mixture wasstirred at room temperature for 4 h and concentrated under reducedpressure. Trifluoroacetic acid 0.7 ml and triethylsilane 212 mg wereadded to the residue. The mixture was stirred for 80 min. 1N-HCl andthen potassium hydroxide pellets were added to the reaction mixture withcooling in ice to alkaline. The mixture was extracted with chloroform.The organic layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue obtainedwas chromatographed on aluminum oxide in chloroform:hexane (4:1) to givethe titled compound as crystals, 158 mg (yield 58%). The crudecrystalline materials were recrystallized from hexane-ethyl acetate togive pale yellow crystals, m.p. 171-173° C.(dec.).

[0262]¹H-NMR(CDCl₃): 1.46 (9H, s), 2.84-2.93 (1H, m), 3.17-3.24 (2H, m),3.59-3.66 (1H, m), 4.23 (1H, dd, J=12.3, 7.2 Hz), 4.37 (1H, d, J=12.3Hz), 6.21 (1H, br s), 6.61 (1H, d, J=7.5 Hz), 6.96-7.08 (3H, m), 8.11(1H, br s)

EXAMPLE A

[0263] As examples of a compound (I), compounds (I-a) and compounds(I-b) shown in Table 7-28 and Table 29-42, respectively. TABLE 7 (I-a)

Compd No R⁴ R⁷ R⁸ 1 COOH H H 2 COOMe H H 3 COOEt H H 4 COO-tBu H H 5CONH₂ H H 6 CONHMe H H 7 CONHEt H H 8 CONH-nPr H H 9 CONMe₂ H H 10CONEt₂ H H 11 CON(nPr)₂ H H 12 CONHPh H H 13

H H 14

H H 15

H H 16 NH₂ H H 17 NHMe H H 18 NHEt H H 19 NH-nPr H H 20 NMe₂ H H 21 NEt₂H H 22 N(nPr)₂ H H 23

H H 24

H H 25

H H 26 NHCOMe H H 27 NHCOEt H H

[0264] TABLE 8 Compd No R⁴ R⁷ R⁸ 1 NHCO-nPr H H 2 NHCOPh H H 3 NMeCOMe HH 4 N(nPr)COMe H H 5 NMeCOPh H H 6 N(nPr)COPh H H 7 NHCOOMe H H 8NHCOOEt H H 9 NHCOO-tBu H H 10 NHCOOCH₂Ph H H 11 NMeCOOMe H H 12N(nPr)COOMe H H 13 NMeCOOOH₂Ph H H 14 N(nPr)COOCH₂Ph H H 15 NHSO₂Me H H16 NHSO₂Et H H 17 NHSO₂Ph H H 18 NHTs H H 19 NMeSO₂Me H H 20 N(nPr)SO₂MeH H 21 NMeSO₂Ph H H 22 N(nPr)SO₂Ph H H 23 COOH Me H 24 COOMe Me H 25COOEt Et H 26 COO-tBu nPr H 27 CONH₂ Me H 28 CONHMe Me H 29 CONHEt Et H30 CONH-nPr nPr H 31 CONMe₂ Me H 32 CONEt₂ Et H 33 CON(nPr)₂ nPr H 34CONHPh Me H 35

Me H 36

Et H 37

nPr H 38 NH₂ Me H 39 NHMe Me H 40 NHEt Et H

[0265] TABLE 9 Compd No R⁴ R⁷ R⁸ 1 NH-nPr nPr H 2 NMe₂ Me H 3 NEt₂ Et H4 N(nPr)₂ nPr H 5

Me H 6

Et H 7

nPr H 8 NHCOMe Me H 9 NHCOEt Et H 10 NHCO-nPr nPr H 11 NHCOPh Me H 12NMeCOMe Me H 13 N(nPr)COMe Et H 14 NMeOOPh nPr H 15 N(nPr)COPh Me H 16NHCOOMe Me H 17 NHCOOEt Et H 18 NHCOO-tBu nPr H 19 NHCOOOH₂Ph Me H 20NMeCOOMe nPr H 21 N(nPr)COOMe nPr H 22 NMeCOOCH₂Ph Me H 23N(nPr)COOCH₂Ph nPr H 24 NHSO₂Me Me H 25 NHSO₂Et Et H 26 NHSO₂Ph nPr H 27NHTs Et H 28 NMeSO₂Me Me H 29 N(nPr)SO₂Me nPr H 30 NMeSO₂Ph Me H 31N(nPr)SO₂Ph Me H 32 COOH Br H 33 COOMe Br H 34 COOEt CN H 35 COO-tBu BrH 36 CONH₂ Br H 37 CONHMe Br H 38 CONHEt CN H 39 CONHnPr Br H 40 CONMe₂Br H 41 CONEt₂ ON H 42 CON(nPr)₂ Br H

[0266] TABLE 10 Compd No R⁴ R⁷ R⁸ 1 CONHPh CN H 2

Br H 3

Br H 4

CN H 5 NH₂ Br H 6 NHMe Br H 7 NHEt CN H 8 NH-nPr Br H 9 NMe₂ Br H 10NEt₂ CN H 11 N(nPr)₂ Br H 12

Br H 13

CN H 14

Br H 15 NHCOMe Br H 16 NHCOEt Br H 17 NHCO-nPr CN H 18 NHCOPh Br H 19NMeCOMe Br H 20 N(nPr)COMe Br H 21 NMeCOPh CN H 22 N(nPr)COPh Br H 23NHCOOMe Br H 24 NHCOOEt CN H 25 NHCOO-tBu Br H 26 NHCOOCH₂Ph Br H 27NMeCOOMe CN H 28 N(nPr)COOMe Br H 29 NMeCOOCH₂Ph Br H 30 N(nPr)COOCH₂PhCN H 31 NHSO₂Me Br H 32 NHSO₂Et Br H 33 NHSO₂Ph Br H 34 NHTs CN H 35NMeSO₂Me Br H 36 N(nPr)SO₂Me Br H 37 NMeSO₂Ph Br H 38 N(nPr)SO₂Ph CN H39 COOH Ph H

[0267] TABLE 11 Compd No R⁴ R⁷ R⁸ 1 COOMe Ph H 2 COOEt Ph H 3 COO-tBu PhH 4 CONH₂ Ph H 5 CONHMe Ph H 6 CONHEt Ph H 7 CONH-nPr Ph H 8 CONMe₂ Ph H9 CONEt₂ Ph H 10 CON(nPr)₂ Ph H 11 CONHPh Ph H 12

Ph H 13

Ph H 14

Ph H 15 NH₂ Ph H 16 NHMe Ph H 17 NHEt Ph H 18 NH-nPr Ph H 19 NMe₂ Ph H20 NEt₂ Ph H 21 N(nPr)₂ Ph H 22

Ph H 23

Ph H 24

Ph H 25 NHCOMe Ph H 26 NHCOEt Ph H 27 NHCO-nPr Ph H 28 NHCOPh Ph H 29NMeCOMe Ph H 30 N(nPr)COMe Ph H 31 NMeCOPh Ph H 32 N(nPr)COPh Ph H 33NHCOOMe Ph H 34 NHCOOEt Ph H 35 NHCOO-tBu Ph H 36 NHCOOCH₂Ph Ph H 37NMeCOOMe Ph H 38 N(nPr)COOMe Ph H

[0268] TABLE 12 Compd No R⁴ R⁷ R⁸ 1 NMeCOOCH₂Ph Ph H 2 N(nPr)COOCH₂Ph PhH 3 NHSO₂Me Ph H 4 NHSO₂Et Ph H 5 NHSO₂Ph Ph H 6 NHTs Ph H 7 NMeSO₂Me PhH 8 N(nPr)SO₂Me Ph H 9 NMeSO₂Ph Ph H 10 N(nPr)SO₂Ph Ph H 11 COOH H Me 12COOMe H Me 13 COOEt H Me 14 COO-tBu H Me 15 CONH₂ H Me 16 CONHMe H Me 17CONHEt H Me 18 CONHnPr H Me 19 CONMe₂ H Me 20 CONEt₂ H Me 21 CON(nPr)₂ HMe 22 CONHPh H Me 23

H Me 24

H Me 25

H Me 26 NH₂ H Me 27 NHMe H Me 28 NHEt H Me 29 NH-nPr H Me 30 NMe₂ H Me31 NEt₂ H Me 32 N(nPr)₂ H Me 33

H Me 34

H Me 35

H Me 36 NHCOMe H Me 37 NHCOEt H Me

[0269] TABLE 13 Compd No R4 R7 R8 1 NHCO-nPr H Me 2 NHCOPh H Me 3NMeCOMe H Me 4 N(nPr)COMe H Me 5 NMeCOPh H Me 6 N(nPr)COPh H Me 7NHCOOMe H Me 8 NHCOOEt H Me 9 NHCOO-tBu H Me 10 NHCOOCH₂Ph H Me 11NMeCOOMe H Me 12 N(nPr)COOMe H Me 13 NMeCOOCH₂Ph H Me 14 N(nPr)COOCH₂PhH Me 15 NHSO₂Me H Me 16 NHSO₂Et H Me 17 NHSO₂Ph H Me 18 NHTs H Me 19NMeSO₂Me H Me 20 N(nPr)SO₂Me H Me 21 NMeSO₂Ph H Me 22 N(nPr)SO₂Ph H Me23 COOH Me Me 24 COOMe Me Me 25 COOEt Et Me 26 COO-tBu Me Me 27 CONH₂nPr Me 28 CONHMe Me Me 29 CONHEt Et Me 30 CONH-nPr nPr Me 31 CONMe₂ MeMe 32 CONEt₂ Et Me 33 CON(nPr)₂ nPr Me 34 CONHPh Me Me 35

Me Me 36

Et Me 37

nPr Me

[0270] TABLE 14 Compd No R⁴ R⁷ R⁸ 1 NH₂ Me Me 2 NHMe Me Me 3 NHEt Me Me4 NH-nPr Et Me 5 NMe₂ Me Me 6 NEt₂ nPr Me 7 N(nPr)₂ nPr Me 8

Me Me 9

Et Me 10

Me Me 11 NHCOMe nPr Me 12 NHCOEt Me Me 13 NHCO-nPr Et Me 14 NHCOPh Me Me15 NMeCOMe nPr Me 16 N(nPr)COMe Me Me 17 NMeCOPh Et Me 18 N(nPr)COPh MeMe 19 NHCOOMe nPr Me 20 NHCOOEt Me Me 21 NHCOO-tBu Et Me 22 NHCOOCH₂PhMe Me 23 NMeCOOMe nPr Me 24 N(nPr)COOMe Me Me 25 NMeCOOCH₂Ph nPr Me 26N(nPr)COOCH₂Ph Me Me 27 NHSO₂Me Et Me 28 NHSO₂Et nPr Me 29 NHSO₂Ph Me Me30 NHTs nPr Me 31 NMeSO₂Me Me Me 32 N(nPr)SO₂Me Et Me 33 NMeSO₂Ph Me Me34 N(nPr)SO₂Ph Et Me 35 COOH Br Me 36 COOMe Br Me 37 COOEt CN Me 38COO-tBu CN Me

[0271] TABLE 15 Compd No R⁴ R⁷ R⁸ 1 CONH₂ Br Me 2 CONHMe Br Me 3 CONHEtCN Me 4 CONH-nPr Br Me 5 CONMe₂ Br Me 6 CONEt₂ CN Me 7 CON(nPr)₂ Br Me 8CONHPh CN Me 9

Br Me 10

CN Me 11

Br Me 12 NH₂ Br Me 13 NHMe CN Me 14 NHEt CN Me 15 NH-nPr Br Me 16 NMe₂Br Me 17 NEt₂ CN Me 18 N(nPr)₂ Br Me 19

Br Me 20

CN Me 21

Br Me 22 NHCOMe Br Me 23 NHCOEt Br Me 24 NHCO-nPr CN Me 25 NHCOPh Br Me26 NMeCOMe Br Me 27 N(nPr)COMe CN Me 28 NMeCOPh Br Me 29 N(nPr)COPh BrMe 30 NHCOOMe CN Me 31 NHCOOEt Br Me 32 NHCOO-tBu Br Me 33 NHCOOCH₂Ph BrMe 34 NMeCOOMe CN Me 35 N(nPr)COOMe Br Me

[0272] TABLE 16 Compd No R⁴ R⁷ R⁸ 1 NMeCOOCH₂Ph Br Me 2 N(nPr)COOCH₂PhCN Me 3 NHSO₂Me Br Me 4 NHSO₂Et Br Me 5 NHSO2Ph CN Me 6 NHTs Br Me 7NMeSO₂Me Br Me 8 N(nPr)SO₂Me CN Me 9 NMeSO₂Ph Br Me 10 N(nPr)SO₂Ph Br Me11 COOH Ph Me 12 COOMe Ph Me 13 COOEt Ph Me 14 COO-tBu Ph Me 15 CONH₂ PhMe 16 CONHMe Ph Me 17 CONHEt Ph Me 18 CONH-nPr Ph Me 19 CONMe₂ Ph Me 20CONEt₂ Ph Me 21 CON(nPr)₂ Ph Me 22 CONHPh Ph Me 23

Ph Me 24

Ph Me 25

Ph Me 26 NH₂ Ph Me 27 NHMe Ph Me 28 NHEt Ph Me 29 NH-nPr Ph Me 30 NMe₂Ph Me 31 NEt₂ Ph Me 32 N(nPr)₂ Ph Me 33

Ph Me 34

Ph Me 35

Ph Me

[0273] TABLE 17 Compd No R⁴ R⁷ R⁸ 1 NHCOMe Ph Me 2 NHCOEt Ph Me 3NHCO-nPr Ph Me 4 NHCOPh Ph Me 5 NMeCOMe Ph Me 6 N(nPr)COMe Ph Me 7NMeCOPh Ph Me 8 N(nPr)COPh Ph Me 9 NHCOOMe Ph Me 10 NHCOOEt Ph Me 11NHCOO-tBu Ph Me 12 NHCOOCH₂Ph Ph Me 13 NMeCOOMe Ph Me 14 N(nPr)COOMe PhMe 15 NMeCOOCH₂Ph Ph Me 16 N(nPr)COOCH₂Ph Ph Me 17 NHSO₂Me Ph Me 18NHSO₂Et Ph Me 19 NHSO₂Ph Ph Me 20 NHTs Ph Me 21 NMeSO₂Me Ph Me 22N(nPr)SO₂Me Ph Me 23 NMeSO₂Ph Ph Me 24 N(nPr)SO₂Ph Ph Me 25 COOH H COPh26 COOMe H COPh 27 COOEt H COPh 28 COO-tBu H COPh 29 CONH₂ H COPh 30CONHMe H COPh 31 CONHEt H COPh 32 CONH-nPr H COPh 33 CONMe₂ H COPh 34CONEt₂ H COPh 35 CON(nPr)₂ H COPh 36 CONHPh H COPh 37

H COPh 38

H COPh 39

H COPh

[0274] TABLE 18 Compd No R⁴ R⁷ R⁸ 1 NH₂ H COPh 2 NHMe H COPh 3 NHEt HCOPh 4 NH-nPr H COPh 5 NMe₂ H COPh 6 NEt₂ H COPh 7 N(nPr)₂ H COPh 8

H COPh 9

H COPh 10

H COPh 11 NHCOMe H COPh 12 NHCOEt H COPh 13 NHCO-nPr H COPh 14 NHCOPh HCOPh 15 NMeCOMe H COPh 16 N(nPr)COMe H COPh 17 NMeCOPh H COPh 18N(nPr)COPh H COPh 19 NHCOOMe H COPh 20 NHCOOEt H COPh 21 NHCOO-tBu HCOPh 22 NHCOOCH₂Ph H COPh 23 NMeCOOMe H COPh 24 N(nPr)COOMe H COPh 25NMeCOOCH₂Ph H COPh 26 N(nPr)COOCH₂Ph H COPh 27 NHSO₂Me H COPh 28 NHSO₂EtH COPh 29 NHSO₂Ph H COPh 30 NHTs H COPh 31 NMeSO₂Me H COPh 32N(nPr)SO₂Me H COPh 33 NMeSO₂Ph H COPh 34 N(nPr)SO₂Ph H COPh 35 COOH MeCOPh 36 COOMe Me COPh 37 COOEt Et COPh 38 COO-tBu nPr COPh 39 CONH₂ MeCOPh

[0275] TABLE 19 Compd No R⁴ R⁷ R⁸ 1 CONHMe Et COPh 2 CONHEt nPr COPh 3CONH-nPr Me COPh 4 CONMe₂ Et COPh 5 CONEt₂ nPr COPh 6 CON(nPr)₂ nPr COPh7 CONHPh Me COPh 8

nPr COPh 9

Et COPh 10

Me COPh 11 NH₂ Et COPh 12 NHMe Me COPh 13 NHEt Et COPh 14 NH-nPr nPrCOPh 15 NMe₂ Me COPh 16 NEt₂ Et COPh 17 N(nPr)₂ nPr COPh 18

Me COPh 19

Me COPh 20

Me COPh 21 NHCOMe Et COPh 22 NHCOEt Et COPh 23 NHCO-nPr Et COPh 24NHCOPh nPr COPh 25 NMeCOMe nPr COPh 26 N(nPr)COMe nPr COPh 27 NMeCOPh EtCOPh 28 N(nPr)COPh Et COPh 29 NHCOOMe Et COPh 30 NHCOOEt Me COPh 31NHCOO-tBu Me COPh 32 NHCOOCH₂Ph Me COPh 33 NMeCOOMe Et COPh 34N(nPr)COOMe nPr COPh 35 NMeCOOCH₂Ph nPr COPh 36 N(nPr)COOCH₂Ph nPr COPh37 NHSO₂Me Me COPh 38 NHSO₂Et Et COPh

[0276] TABLE 20 Compd No R⁴ R⁷ R⁸ 1 NHSO₂Ph nPr COPh 2 NHTs Me COPh 3NMeSO₂Me Et COPh 4 N(nPr)SO₂Me nPr COPh 5 NMeSO₂Ph Me COPh 6 N(nPr)SO₂PhMe COPh 7 COOH Br COPh 8 COOMe Br COPh 9 COOEt CN COPh 10 COO-tBu BrCOPh 11 CONH₂ CN COPh 12 CONHMe Br COPh 13 CONHEt CN COPh 14 CONH-nPr BrCOPh 15 CONMe₂ Br COPh 16 CONEt₂ CN COPh 17 CON(nPr)₂ Br COPh 18 CONHPhBr COPh 19

CN COPh 20

Br COPh 21

Br COPh 22 NH₂ CN COPh 23 NHMe Br COPh 24 NHEt CN COPh 25 NH-nPr Br COPh26 NMe₂ Br COPh 27 NEt₂ Br COPh 28 N(nPr)₂ CN COPh 29

Br COPh 30

Br COPh 31

CN COPh 32 NHCOMe Br COPh 33 NHCOEt CN COPh 34 NHCO-nPr Br COPh 35NHCOPh CN COPh 36 NMeCOMe Br COPh 37 N(nPr)COMe CN COPh

[0277] TABLE 21 Compd No R⁴ R⁷ R⁸ 1 NMeCOPh CN COPh 2 N(nPr)COPh Br COPh3 NHCOOMe Br COPh 4 NHCOOEt CN COPh 5 NHCOO-tBu Br COPh 6 NHCOOCH₂Ph BrCOPh 7 NMeCOOMe CN COPh 8 N(nPr)COOMe Br COPh 9 NMeCOOCH₂Ph Br COPh 10N(nPr)COOCH₂Ph CN COPh 11 NHSO₂Me Br COPh 12 NHSO₂Et Br COPh 13 NHSO₂PhCN COPh 14 NHTs Br COPh 15 NMeSO₂Me Br COPh 16 N(nPr)SO₂Me CN COPh 17NMeSO2Ph CN COPh 18 N(nPr)SO₂Ph CN COPh 19 COOH Ph COPh 20 COOMe Ph COPh21 COOEt Ph COPh 22 COO-tBu Ph COPh 23 CONH₂ Ph COPh 24 CONHMe Ph COPh25 CONHEt Ph COPh 26 CONH-nPr Ph COPh 27 CONMe₂ Ph COPh 28 CONEt₂ PhCOPh 29 CON(nPr)₂ Ph COPh 30 CONHPh Ph COPh 31

Ph COPh 32

Ph COPh 33

Ph COPh 34 NH₂ Ph COPh 35 NHMe Ph COPh 36 NHEt Ph COPh

[0278] TABLE 22 Compd No R⁴ R⁷ R⁸ 1 NH-nPr Ph COPh 2 NMe₂ Ph COPh 3 NEt₂Ph COPh 4 N(nPr)₂ Ph COPh 5

Ph COPh 6

Ph COPh 7

Ph COPh 8 NHCOMe Ph COPh 9 NHCOEt Ph COPh 10 NHCO-nPr Ph COPh 11 NHCOPhPh COPh 12 NMeCOMe Ph COPh 13 N(nPr)COMe Ph COPh 14 NMeCOPh Ph COPh 15N(nPr)COPh Ph COPh 16 NHCOOMe Ph COPh 17 NHCOOEt Ph COPh 18 NHCOO-tBu PhCOPh 19 NHCOOCH₂Ph Ph COPh 20 NMeCOOMe Ph COPh 21 N(nPr)COOMe Ph COPh 22NMeCOOCH₂Ph Ph COPh 23 N(nPr)COOCH₂Ph Ph COPh 24 NHSO₂Me Ph COPh 25NHSO₂Et Ph COPh 26 NHSO₂Ph Ph COPh 27 NHTs Ph COPh 28 NMeSO₂Me Ph COPh29 N(nPr)SO₂Me Ph COPh 30 NMeSO₂Ph Ph COPh 31 N(nPr)SO₂Ph Ph COPh 32COOH H SO₂Ph 33 COOMe H SO₂Ph 34 COOEt H SO₂Ph 35 COO-tBu H SO₂Ph 36CONH₂ H SO₂Ph 37 CONHMe H SO₂Ph

[0279] TABLE 23 Compd No R⁴ R⁷ R⁸ 1 CONHEt H SO₂Ph 2 CONH-nPr H SO₂Ph 3CONMe₂ H SO₂Ph 4 CONEt₂ H SO₂Ph 5 CON(nPr)₂ H SO₂Ph 6 CONHPh H SO₂Ph 7

H SO₂Ph 8

H SO₂Ph 9

H SO₂Ph 10 NH₂ H SO₂Ph 11 NHMe H SO₂Ph 12 NHEt H SO₂Ph 13 NH-nPr H SO₂Ph14 NMe₂ H SO₂Ph 15 NEt₂ H SO₂Ph 16 N(nPr)₂ H SO₂Ph 17

H SO₂Ph 18

H SO₂Ph 19

H SO₂Ph 20 NHCOMe H SO₂Ph 21 NHCOEt H SO₂Ph 22 NHCO-nPr H SO₂Ph 23NHCOPh H SO₂Ph 24 NMeCOMe H SO₂Ph 25 N(nPr)COMe H SO₂Ph 26 NMeCOPh HSO₂Ph 27 N(nPr)COPh H SO₂Ph 28 NHCOOMe H SO₂Ph 29 NHCOOEt H SO₂Ph 30NHCOO-tBu H SO₂Ph 31 NHCOOCH₂Ph H SO₂Ph 32 NMeCOOMe H SO₂Ph 33N(nPr)COOMe H SO₂Ph 34 NMeCOOCH₂Ph H SO₂Ph 35 N(nPr)COOCH₂Ph H SO₂Ph 36NHSO₂Me H SO₂Ph 37 NHSO₂Et H SO₂Ph

[0280] TABLE 24 Compd No R⁴ R⁷ R⁸ 1 NHSO₂Ph H SO₂Ph 2 NHTs H SO₂Ph 3NMeSO₂Me H SO₂Ph 4 N(nPr)SO₂Me H SO₂Ph 5 NMeSO₂Ph H SO₂Ph 6 N(nPr)SO₂PhH SO₂Ph 7 COOH Me SO₂Ph 8 COOMe Me SO₂Ph 9 COOEt Et SO₂Ph 10 COO-tBu nPrSO₂Ph 11 CONH₂ Me SO₂Ph 12 CONHMe Me SO₂Ph 13 CONHEt Et SO₂Ph 14CONH-nPr nPr SO₂Ph 15 CONMe₂ Me SO₂Ph 16 CONEt₂ Me SO₂Ph 17 CON(nPr)₂ MeSO₂Ph 18 CONHPh Et SO₂Ph 19

Et SO₂Ph 20

Et SO₂Ph 21

nPr SO₂Ph 22 NH₂ nPr SO₂Ph 23 NHMe nPr SO₂Ph 24 NHEt Et SO₂Ph 25 NH-nPrMe SO₂Ph 26 NMe₂ nPr SO₂Ph 27 NEt₂ Et SO₂Ph 28 N(nPr)₂ Et SO₂Ph 29

Me SO₂Ph 30

Me SO₂Ph 31

Me SO₂Ph 32 NHCOMe Et SO₂Ph 33 NHCOEt Et SO₂Ph 34 NHCO-nPr Et SO₂Ph 35NHCOPh Me SO₂Ph 36 NMeCOMe Me SO₂Ph

[0281] TABLE 25 Compd No R⁴ R⁷ R⁸ 1 N(nPr)COMe Me SO₂Ph 2 NMeCOPh nPrSO₂Ph 3 N(nPr)COPh nPr SO₂Ph 4 NHCOOMe nPr SO₂Ph 5 NHCOOEt Me SO₂Ph 6NHCOO-tBu Et SO₂Ph 7 NHCOOCH₂Ph nPr SO₂Ph 8 NMeCOOMe Me SO₂Ph 9N(nPr)COOMe Et SO₂Ph 10 NMeCOOCH₂Ph nPr SO₂Ph 11 N(nPr)COOCH₂Ph Me SO₂Ph12 NHSO₂Me Et SO₂Ph 13 NHSO₂Et nPr SO₂Ph 14 NHSO₂Ph Me SO₂Ph 15 NHTs MeSO₂Ph 16 NMeSO₂Me Me SO₂Ph 17 N(nPr)SO₂Me nPr SO₂Ph 18 NMeSO₂Ph nPrSO₂Ph 19 N(nPr)SO₂Ph nPr SO₂Ph 20 COOH Br SO₂Ph 21 COOMe CN SO₂Ph 22COOEt Br SO₂Ph 23 COO-tBu CN SO₂Ph 24 CONH² Br SO₂Ph 25 CONHMe Br SO₂Ph26 CONHEt Br SO₂Ph 27 CONH-nPr Br SO₂Ph 28 CONMe₂ CN SO₂Ph 29 CONEt₂ CNSO₂Ph 30 CON(nPr)₂ CN SO₂Ph 31 CONHPh Br SO₂Ph 32

Br SO₂Ph 33

Br SO₂Ph 34

CN SO₂Ph 35 NH₂ Br SO₂Ph 36 NHMe CN SO2Ph

[0282] TABLE 26 Compd No R⁴ R⁷ R⁸ 1 NHEt Br SO₂Ph 2 NH-nPr CN SO₂Ph 3NMe₂ Br SO₂Ph 4 NEt₂ Br SO₂Ph 5 N(nPr)₂ CN SO₂Ph 6

Br SO₂Ph 7

Br SO₂Ph 8

Br SO₂Ph 9 NHCOMe CN SO₂Ph 10 NHCOEt Br SO₂Ph 11 NHCO-nPr CN SO₂Ph 12NHCOPh Br SO₂Ph 13 NMeCOMe Br SO₂Ph 14 N(nPr)COMe CN SO₂Ph 15 NMeCOPh BrSO₂Ph 16 N(nPr)COPh Br SO₂Ph 17 NHCOOMe CN SO₂Ph 18 NHCOOEt Br SO₂Ph 19NHCOO-tBu Br SO₂Ph 20 NHCOOCH₂Ph Br SO₂Ph 21 NMeCOOMe CN SO₂Ph 22N(nPr)COOMe Br SO₂Ph 23 NMeCOOCH₂Ph Br SO₂Ph 24 N(nPr)COOCH₂Ph Br SO₂Ph25 NHSO₂Me CN SO₂Ph 26 NHSO₂Et Br SO₂Ph 27 NHSO₂Ph Br SO₂Ph 28 NHTs CNSO₂Ph 29 NMeSO₂Me Br SO₂Ph 30 N(nPr)SO₂Me Br SO₂Ph 31 NMeSO₂Ph CN SO₂Ph32 N(nPr)SO₂Ph Br SO₂Ph 33 COOH Ph SO₂Ph 34 COOMe Ph SO₂Ph 35 COOEt PhSO₂Ph 36 COO-tBu Ph SO₂Ph 37 CONH₂ Ph SO2Ph

[0283] TABLE 27 Compd No R⁴ R⁷ R⁸ 1 CONHMe Ph SO₂Ph 2 CONHEt Ph SO₂Ph 3CONH-nPr Ph SO₂Ph 4 CONMe₂ Ph SO₂Ph 5 CONEt₂ Ph SO₂Ph 6 CON(nPr)₂ PhSO₂Ph 7 CONHPh Ph SO₂Ph 8

Ph SO₂Ph 9

Ph SO₂Ph 10

Ph SO₂Ph 11 NH₂ Ph SO₂Ph 12 NHMe Ph SO₂Ph 13 NHEt Ph SO₂Ph 14 NH-nPr PhSO₂Ph 15 NMe₂ Ph SO₂Ph 16 NEt₂ Ph SO₂Ph 17 N(nPr)₂ Ph SO₂Ph 18

Ph SO₂Ph 19

Ph SO₂Ph 20

Ph SO₂Ph 21 NHCOMe Ph SO₂Ph 22 NHCOEt Ph SO₂Ph 23 NHCO-nPr Ph SO₂Ph 24NHCOPh Ph SO₂Ph 25 NMeCOMe Ph SO₂Ph 26 N(nPr)COMe Ph SO₂Ph 27 NMeCOPh PhSO₂Ph 28 N(nPr)COPh Ph SO₂Ph 29 NHCOOMe Ph SO₂Ph 30 NHCOOEt Ph SO₂Ph 31NHCOO-tBu Ph SO₂Ph 32 NHCOOCH₂Ph Ph SO₂Ph 33 NMeCOOMe Ph SO₂Ph 34N(nPr)COOMe Ph SO₂Ph 35 NMeCOOCH₂Ph Ph SO₂Ph 36 N(nPr)COOCH₂Ph Ph SO2Ph

[0284] TABLE 28 Compd No R⁴ R⁷ R⁸ 1 NHSO₂Me Ph SO₂Ph 2 NHSO₂Et Ph SO₂Ph3 NHSO₂Ph Ph SO₂Ph 4 NHTs Ph SO₂Ph 5 NMeSO₂Me Ph SO₂Ph 6 N(nPr)SO₂Me PhSO₂Ph 7 NMeSO₂Ph Ph SO₂Ph 8 N(nPr)SO₂Ph Ph SO₂Ph

[0285] TABLE 29 (I-b)

Compd No R⁴ R⁶ R⁷ R⁸ 1 COOH H H H 2 COOMe H H H 3 COOEt H H H 4 COO-tBuH H H 5 CONH₂ H H H 6 CONHMe H H H 7 CONHEt H H H 8 CONH-nPr H H H 9CONMe₂ H H H 10 CONEt₂ H H H 11 CON(nPr)₂ H H H 12 CONHPh H H H 13

H H H 14

H H H 15

H H H 16 NHCOOMe H H H 17 NHCOOEt H H H 18 NHCOO-tBu H H H 19 NHCOOCH₂PhH H H 20 NMeCOOMe H H H 21 N(nPr)COOMe H H H 22 NMeCOOCH₂Ph H H H 23N(nPr)COOCH₂Ph H H H 24 COOH H Me H 25 COOMe H Me H 26 COOEt H Et H

[0286] TABLE 30 Compd No R⁴ R⁶ R⁷ R⁸ 1 COO-tBu H nPr H 2 CONH₂ H Me H 3CONHMe H Me H 4 CONHEt H Et H 5 CONH-nPr H nPr H 6 CONMe₂ H Me H 7CONEt₂ H Me H 8 CON(nPr)₂ H Me H 9 CONHPh H Et H 10

H Et H 11

H Et H 12

H Et H 13 NHCOOMe H nPr H 14 NHCOOEt H nPr H 15 NHCOO-tBu H nPr H 16NHCOOCH₂Ph H Me H 17 NMeCOOMe H Et H 18 N(nPr)COOMe H nPr H 19NMeCOOCH₂Ph H Me H 20 N(nPr)COOCH₂Ph H nPr H 21 COOH H Br H 22 COOMe HBr H 23 COOEt H CN H 24 COO-tBu H Br H 25 CONH₂ H Br H 26 CONHMe H CN H27 CONHEt H Br H 28 CONH-nPr H CN H 29 CONMe₂ H Br H 30 CONEt₂ H Br H 31CON(nPr)₂ H CN H 32 CONHPh H Br H 33

H Br H 34

H CN H 35

H Br H

[0287] TABLE 31 Compd No. R⁴ R⁶ R⁷ R⁸ 1 NHCOOMe H Br H 2 NHCOOEt H CN H3 NHCOO-tBu H Br H 4 NHCOOCH₂Ph H CN H 5 NMeCOOMe H Br H 6 N(nPr)COOMe HCN H 7 NMeCOOCH₂Ph H Br H 8 N(nPr)COOCH₂Ph H CN H 9 COOH H Ph H 10 COOMeH Ph H 11 COOEt H Ph H 12 COO-tBu H Ph H 13 CONH₂ H Ph H 14 CONHMe H PhH 15 CONHEt H Ph H 16 CONH-nPr H Ph H 17 CONMe₂ H Ph H 18 CONEt₂ H Ph H19 CON(nPr)₂ H Ph H 20 CONHPh H Ph H 21

H Ph H 22

H Ph H 23

H Ph H 24 NHCOOMe H Ph H 25 NHCOOEt H Ph H 26 NHCOO-tBu H Ph H 27NHCOOCH₂Ph H Ph H 28 NMeCOOMe H Ph H 29 N(nPr)COOMe H Ph H 30NMeCOOCH₂Ph H Ph H 31 N(nPr)COOCH₂Ph H Ph H 32 COOH H H Me 33 COOMe H HMe 34 COOEt H H Me 35 COO-tBu H H Me 36 CONH₂ H H Me 37 CONHMe H H Me

[0288] TABLE 32 Compd No R⁴ R⁶ R⁷ R⁸ 1 CONHEt H H Me 2 CONH-nPr H H Me 3CONMe₂ H H Me 4 CONEt₂ H H Me 5 CON(nPr)₂ H H Me 6 CONHPh H H Me 7

H H Me 8

H H Me 9

H H Me 10 NHCOOMe H H Me 11 NHCOOEt H H Me 12 NHCOO-tBu H H Me 13NHCOOCH₂Ph H H Me 14 NMeCOOMe H H Me 15 N(nPr)COOMe H H Me 16NMeCOOCH₂Ph H H Me 17 N(nPr)COOCH₂Ph H H Me 18 COOH H Me Me 19 COOMe HMe Me 20 COOEt H Et Me 21 COO-tBu H nPr Me 22 CONH₂ H Me Me 23 CONHMe HMe Me 24 CONHEt H Me Me 25 CONH-nPr H Et Me 26 CONMe₂ H Et Me 27 CONEt₂H Et Me 28 CON(nPr)₂ H nPr Me 29 CONHPh H nPr Me 30

H nPr Me 31

H Me Me 32

H Et Me 33 NHCOOMe H nPr Me 34 NHCOOEt H Me Me

[0289] TABLE 33 Compd No R⁴ R⁶ R⁷ R⁸ 1 NHCOO-tBu H Et Me 2 NHCOOCH₂Ph HnPr Me 3 NMeCOOMe H Me Me 4 N(nPr)COOMe H Me Me 5 NMeCOOCH₂Ph H Et Me 6N(nPr)COOCH₂Ph H nPr Me 7 COOH H Br Me 8 COOMe H CN Me 9 COOEt H Br Me10 COO-tBu H CN Me 11 CONH₂ H Br Me 12 CONHMe H CN Me 13 CONHEt H Br Me14 CONH-nPr H CN Me 15 CONMe₂ H Br Me 16 CONEt₂ H CN Me 17 CON(nPr)₂ HBr Me 18 CONHPh H CN Me 19

H Br Me 20

H Br Me 21

H CN Me 22 NHCOOMe H CN Me 23 NHCOOEt H Br Me 24 NHCOO-tBu H CN Me 25NHCOOCH₂Ph H Br Me 26 NMeCOOMe H Br Me 27 N(nPr)COOMe H CN Me 28NMeCOOCH₂Ph H Br Me 29 N(nPr)COOCH₂Ph H Br Me 30 COOH H Ph Me 31 COOMe HPh Me 32 COOEt H Ph Me 33 COO-tBu H Ph Me 34 CONH₂ H Ph Me 35 CONHMe HPh Me 36 CONHEt H Ph Me 37 CONH-nPr H Ph Me

[0290] TABLE 34 Compd No R⁴ R⁶ R⁷ R⁸ 1 CONMe₂ H Ph Me 2 CONEt₂ H Ph Me 3CON(nPr)₂ H Ph Me 4 CONHPh H Ph Me 5

H Ph Me 6

H Ph Me 7

H Ph Me 8 NHCOOMe H Ph Me 9 NHCOOEt H Ph Me 10 NHCOO-tBu H Ph Me 11NHCOOCH₂Ph H Ph Me 12 NMeCOOMe H Ph Me 13 N(nPr)COOMe H Ph Me 14NMeCOOCH₂Ph H Ph Me 15 N(nPr)COOCH₂Ph H Ph Me 16 COOH H H COPh 17 COOMeH H COPh 18 COOEt H H COPh 19 COO-tBu H H COPh 20 CONH₂ H H COPh 21CONHMe H H COPh 22 CONHEt H H COPh 23 CONH-nPr H H COPh 24 CONMe₂ H HCOPh 25 CONEt₂ H H COPh 26 CON(nPr)₂ H H COPh 27 CONHPh H H COPh 28

H H COPh 29

H H COPh 30

H H COPh 31 NHCOOMe H H COPh 32 NHCOOEt H H COPh 33 NHCOO-tBu H H COPh34 NHCOOCH₂Ph H H COPh

[0291] TABLE 35 Compd No R⁴ R⁶ R⁷ R⁸ 1 NMeCOOMe H H COPh 2 N(nPr)COOMe HH COPh 3 NMeCOOCH₂Ph H H COPh 4 N(nPr)COOCH₂Ph H H COPh 5 COOH H Me COPh6 COOMe H nPr COPh 7 COOEt H Et COPh 8 COO-tBu H Et COPh 9 CONH₂ H EtCOPh 10 CONHMe H Me COPh 11 CONHEt H Me COPh 12 CONH-nPr H Me COPh 13CONMe₂ H nPr COPh 14 CONEt₂ H nPr COPh 15 CON(nPr)₂ H nPr COPh 16 CONHPhH Me COPh 17

H Et COPh 18

H nPr COPh 19

H Me COPh 20 NHCOOMe H Me COPh 21 NHCOOEt H Me COPh 22 NHCOO-tBu H EtCOPh 23 NHCOOCH₂Ph H nPr COPh 24 NMeCOOMe H Et COPh 25 N(nPr)COOMe H nPrCOPh 26 NMeCOOCH₂Ph H Me COPh 27 N(nPr)COOCH₂Ph H Me COPh 28 COOH H BrCOPh 29 COOMe H CN COPh 30 COOEt H Br COPh 31 COO-tBu H CN COPh 32 CONH₂H Br COPh 33 CONHMe H Br COPh 34 CONHEt H CN COPh 35 CONH-nPr H CN COPh36 CONMe₂ H Br COPh

[0292] TABLE 36 Compd No R⁴ R⁶ R⁷ R⁸  1 CONEt₂ H Br COPh  2 CON(nPr)₂ HBr COPh  3 CONHPh H Br COPh  4

H CN COPh  5

H CN COPh  6

H Br COPh  7 NHCOOMe H CN COPh  8 NHCOOEt H Br COPh  9 NHCOO-tBu H CNCOPh 10 NHOCOCH₂Ph H Br COPh 11 NMeCOOMe H CN COPh 12 N(nPr)COOMe H BrCOPh 13 NMeOCOCH₂Ph H Br COPh 14 N(nPr)OCOCH₂Ph H Br COPh 15 COOH H PhCOPh 16 COOMe H Ph COPh 17 COOEt H Ph COPh 18 COO-tBu H Ph COPh 19 CONH₂H Ph COPh 20 CONHMe H Ph COPh 21 CONHEt H Ph COPh 22 CONH-nPr H Ph COPh23 CONMe₂ H Ph COPh 24 CONEt₂ H Ph COPh 25 CON(nPr)₂ H Ph COPh 26 CONHPhH Ph COPh 27

H Ph COPh 28

H Ph COPh 29

H Ph COPh 30 NHCOOMe H Ph COPh 31 NHCOOEt H Ph COPh 32 NHCOO-tBu H PhCOPh

[0293] TABLE 37 Compd No R⁴ R⁶ R⁷ R⁸  1 NHCOOCH₂Ph H Ph COPh  2 NMeCOOMeH Ph COPh  3 N(nPr)COOMe H Ph COPh  4 NMeCOOCH₂Ph H Ph COPh  5N(nPr)COOCH₂Ph H Ph COPh  6 COOH H H SO₂Ph  7 COOMe H H SO₂Ph  8 COOEt HH SO₂Ph  9 COO-tBu H H SO₂Ph 10 CONH2 H H SO₂Ph 11 CONHMe H H SO₂Ph 12CONHEt H H SO₂Ph 13 CONHnPr H H SO₂Ph 14 CONMe₂ H H SO₂Ph 15 CONEt₂ H HSO₂Ph 16 CON(nPr)₂ H H SO₂Ph 17 CONHPh H H SO₂Ph 18

H H SO₂Ph 19

H H SO₂Ph 20

H H SO₂Ph 21 NHCOOMe H H SO₂Ph 22 NHCOOEt H H SO₂Ph 23 NHCOO-tBu H HSO₂Ph 24 NHCOOCH₂Ph H H SO₂Ph 25 NMeCOOMe H H SO₂Ph 26 N(nPr)COOMe H HSO₂Ph 27 NMeCOOCH₂Ph H H SO₂Ph 28 N(nPr)COOCH₂Ph H H SO₂Ph 29 COOH H MeSO₂Ph 30 COOMe H Et SO₂Ph 31 COOEt H nPr SO₂Ph 32 COO-tBu H Ft SO₂Ph 33CONH₂ H nPr SO₂Ph 34 CONHMe H Me SO₂Ph 35 CONHEt H Me SO₂Ph 36 CONH-nPrH nPr SO₂Ph

[0294] TABLE 38 Compd No R⁴ R⁶ R⁷ R⁸  1 CONMe₂ H nPr SO₂Ph  2 CONEt₂ HEt SO₂PII  3 CON(nPr)₂ H Et SO₂Ph  4 CONHPh H nPr SO₂Ph  5

H nPr SO₂Ph  6

H nPr SO₂Ph  7

H Me SO₂Ph  8 NHCOOMe H Me SO₂Ph  9 NHCOOEt H Me SO₂Ph 10 NHCOO-tBu H EtSO₂Ph 11 NHCOOCH₂Ph H Et SO₂Ph 12 NMeCOOMe H Et SO₂Ph 13 N(nPr)COOMe HMe SO₂Ph 14 NMeOCOCH₂Ph H Me SO₂Ph 15 N(nPr)COOCH₂Ph H Me SO₂PIi 16 COOHH Br SO₂Ph 17 COOMe H Br SO₂Ph 18 COOEt H Br SO₂Ph 19 COO-tBu H CN SO₂Ph20 CONH₂ H Br SO₂Ph 21 CONHMe H Br SO₂PIi 22 CONHEt H Br SO₂Ph 23CONH-nPr H CN SO₂Ph 24 CONMe₂ H Br SO₂Ph 25 CONEt₂ H Br SO₂Ph 26CON(nPr)₂ H Br SO₂Ph 27 CONHPh H CN SO₂Ph 28

H Br SO₂Ph 29

H Br SO₂Ph 30

H Br SO₂Ph 31 NHCOOMe H Br SO₂Ph 32 NHCOOEt H CN SO₂Ph 33 NHCOO-tBu H BrSO₂Ph

[0295] TABLE 39 Compd No R⁴ R⁶ R⁷ R⁸  1 NHCOOCH₂Ph H Br SO₂Ph  2NMeCOOMe H Br SO₂Ph  3 N(nPr)COOMe H CN SO₂Ph  4 NMeCOOCH₂Ph H Br SO₂Ph 5 N(nPr)COOCH₂Ph H Br SO₂Ph  6 COOH H Ph SO₂Ph  7 COOMe H Ph SO₂Ph  8COOEt H Ph SO₂Ph  9 COO-tBu H Ph SO₂Ph 10 CONH₂ H Ph SO₂Ph 11 CONHMe HPh SO₂Ph 12 CONHEt H Ph SO₂Ph 13 CONH-nPr H Ph SO₂Ph 14 CONMe₂ H PhSO₂Ph 15 CONEt₂ H Ph SO₂Ph 16 CON(nPr)₂ H Ph SO₂Ph 17 CONHPh H Ph SO₂Ph18

H Ph SO₂Ph 19

H Ph SO₂Ph 20

H Ph SO₂Ph 21 NHCOOMe H Ph SO₂Ph 22 NHCOOEt H Ph SO₂Ph 23 NHCOO-tBu H PhSO₂Ph 24 NHCOOCH₂Ph H Ph SO₂Ph 25 NMeCOOMe H Ph SO₂Ph 26 N(nPr)COOMe HPh SO₂Ph 27 NMeCOOCH₂Ph H Ph SO₂Ph 28 N(nPr)COOCH₂Ph H Ph SO₂Ph 29 OHCOOMe H H 30 OMe COOMe H H 31 OH COOMe Me H 32 OMe COOMe Me H 33 OHCOOMe Br H 34 OMe COOMe Br H 35 OH COOMe Ph H 36 OMe COOMe Ph H 37 OHCOOMe H Me 38 OMe COOMe H Me

[0296] TABLE 40 Comp No R⁴ R⁶ R⁷ R⁸ 1 OH COOMe Me Me 2 OMe COOMe Et Me 3OH COOMe Br Me 4 OMe COOMe Br Me 5 OH COOMe Ph Me 6 OMe COOMe Ph Me 7 OHCOOMe H COPh 8 OMe COOMe H COPh 9 OH COOMe Me COPh 10 OMe COOMe nPr COPh11 OH COOMe Br COPh 12 OMe COOMe CN COPh 13 OH COOMe CN COPh 14 OMeCOOMe Ph COPh 15 OH COOMe H SO₂Ph 16 OMe COOMe CN SO₂Ph 17 OH COOMe EtSO₂Ph 18 OMe COOMe Me SO₂Ph 19 OH COOMe CN SO₂Ph 20 OMe COOMe Br SO₂Ph21 OH COOMe Ph SO₂Ph 22 OMe COOMe CN SO₂Ph 23 OH COOEt H H 24 OMe COOEtH H 25 OH COOEt nPr H 26 OMe COOEt Et H 27 OH COOEt Br H 28 OMe COOEt CNH 29 OH COOEt Ph H 30 OMe COOEt CN H 31 OH COOEt H Me 32 OMe COOEt H Me33 OH COOEt nPr Me 34 OMe COOEt CN Me 35 OH COOEt Br Me 36 OMe COOEt CNMe 37 OH COOEt Ph Me 38 OMe COOEt Ph Me 39 OH COOEt H COPh 40 OMe COOEtCN COPh 41 OH COOEt Me COPh

[0297] TABLE 41 Comp No R⁴ R⁶ R⁷ R⁸ 1 OMe COOEt Et COPh 2 OH COOEt BrCOPh 3 OMe COOEt CN COPh 4 OH COOEt Ph COPh 5 OMe COOEt CN COPh 6 OHOQOEt H SO₂Ph 7 OMe OQOEt H SO₂Ph 8 OH COOEt Me SO₂Ph 9 OMe COOEt nPrSO₂Ph 10 OH COOEt CN SO₂Ph 11 OMe COOEt Br SO₂Ph 12 OH COOEt Ph SO₂Ph 13OMe COOEt Ph SO₂Ph 14 OH CN H H 15 OMe CN CN H 16 OH CN Me H 17 OMe CNEt H 18 OH CN Br H 19 OMe CN CN H 20 OH CN Ph H 21 OMe CN Ph H 22 OH CNH Me 23 OMe CN H Me 24 OH CN CN Me 25 OMe CN Me Me 26 OH CN Br Me 27 OMeCN Br Me 28 OH CN Ph Me 29 OMe CN CN Me 30 OH CN H COPh 31 OMe CN H COPh32 OH CN CN COPh 33 OMe CN Et COPh 34 OH CN Br COPh 35 OMe CN Br COPh 36OH CN Ph COPh 37 OMe CN CN COPh 38 OH CN H SO₂Ph 39 OMe CN H SO₂Ph 40 OHCN nPr SO₂Ph 41 OMe CN nPr SO₂Ph

[0298] TABLE 42 Comp No R⁴ R⁶ R⁷ R⁸ 1 OH CN Br SO₂Ph 2 OMe CN Br SO₂Ph 3OH CN CN SO₂Ph 4 OMe CN Ph SO₂Ph 5 OH CH₂NH₂ H H 6 OMe CH₂NH₂ H H 7 OHCH₂NH₂ nPr H 8 OMe CH₂NH₂ Me H 9 OH CH₂NH₂ Br H 10 OMe CH₂NH₂ CN H 11 OHCH₂NH₂ Ph H 12 OMe CH₂NH₂ Ph H 13 OH CH₂NH₂ CN Me 14 OMe CH₂NH₂ H Me 15OH CH₂NH₂ Et Me 16 OMe CH₂NH₂ CN Me 17 OH CH₂NH₂ Br Me 18 OMe CH₂NH₂ BrMe 19 OH CH₂NH₂ Ph Me 20 OMe CH₂NH₂ CN Me 21 OH CH₂NH₂ H COPh 22 OMeCH₂NH₂ H COPh 23 OH CH₂NH₂ nPr COPh 24 OMe CH₂NH₂ nPr COPh 25 OH CH₂NH₂Br COPh 26 OMe CH₂NH₂ Br COPh 27 OH CH₂NH₂ Ph COPh 28 OMe CH₂NH₂ Ph COPh29 OH CH₂NH₂ H SO₂Ph 30 OMe CH₂NH₂ H SO₂Ph 31 OH CH₂NH₂ Me SO₂Ph 32 OMeCH₂NH₂ Me SO₂Ph 33 OH CH₂NH₂ CN SO₂Ph 34 OMe CH₂NH₂ Br SO₂Ph 35 OHCH₂NH₂ CN SO₂Ph 36 OMe CH₂NH₂ Ph SO₂Ph

[0299] Experimentals

[0300] A mixture of radioactive ligands and some cardinal numbers oftest compounds was incubated with a sample of cell membrane, which wasprepared from brain of rats or HEK293 cells, which expressed thereceptor, under the following conditions. Then, the sample was filteredby suction on a Whatman GF/C. Radioactivity on the filter wasencountered by the use of a liquid scintillation counter. 50% Inhibitoryconcentration values (IC₅₀ values) of each selective binding werecalculated for test compounds and the Ki value was obtained by applyingan equation of Cheng-Prusoff [Biochem. Pharmacol. 22 (1973) 3099-3108]Ki=IC₅₀/(1+[L]/Kd). [L] represents a concentration of the radio ligandused and Kd shows dissociation constant. TABLE 43 Condition of ReceptorOrigin Radioactive Ligand Incubation 5-HT1A Rat 1 nM [³H] 8-OH- 25° C.30 min hippocampus DPAT 5-HT2 Rat cerebral 1 nM [³H] Ketanserin 37° C.30 min cortex 5-HT6 rat5-HT₆ 8 nM [³H] 5HT 25° C. 120 min (HEK293) 4 nM[³H] LSD 37° C. 60 min 5-HT7 Human 5-HT₇ 0.5 nM [³H] 5CT 25° C. 120 min(HEK293)

[0301] TABLE 44 Ki value (nM) ±SE Example Compd. No. 5-HT1A 5-HT6 5-HT75 8-1 36 12 19-1  81 12 19-2  23 97 12 19-3  5.7 46 12 19-5  10 12 19-7 19 12 19-10 2.5 12 19-15 7.7 4.6 16 12 19-16 58 62 86 12 19-18 2.7 1219-19 3.8 13 20-1  1.7 13 20-5  0.49 13 20-6  2.7 13 20-9  86 78 1320-10 95 45 13 20-11 5.7 13 20-12 2.7 13 20-13 3.9 13 20-14 22 13 20-1529 13 20-16 22 13 20-17 29 13 20-18 22 13 20-19 12 13 20-20 11 13 20-212.7 13 20-22 26 13 20-23 9.9 13 20-24 3.2 13 20-25 36 14 21 14 24 36-1 29 65 24 36-2  8.5 24 36-3  58 4.2 24 36-4  26 38 83 22 27 39 27 73 2840 15 32 74 29 41 57 34 46-2  34 46-3  18 34 46-1  28 35 47 78 36 48 1

[0302] Industrial Applicability

[0303] Having an affinity against serotonin receptors, compoundsdescribed in this invention are useful as medicines such as therapeuticagents of diseases for central nervous systems thereof. Furthermore,these compounds are useful as synthetic intermediates thereof.

1. A compound, prodrug, pharmaceutically acceptable salt or solvatethereof of the formula:

wherein R¹ is hydrogen; R² is hydrogen or lower alkyl; R³ is hydrogen,—COOR¹² (R¹² is hydrogen or ester moiety) or —CN; R⁴ is hydrogen, loweralkyl, —COOR¹³ (R¹³ is hydrogen or ester moiety), 13 CONR¹⁴R¹⁵ (R¹⁴ andR¹⁵ are each independently hydrogen, lower alkyl, cycloalkyl, loweralkenyl, optionally substituted aralkyl, optionally substituted aryl oroptionally substituted heteroaryl, or R¹⁴ and R¹⁵ taken together mayform a 5- to 7-membered heterocycle ring with the neighboring nitrogenatom), —CN, —NO₂, —NR¹⁶R¹⁷ (R¹⁶ and R¹⁷ are each independently hydrogen,—CN, optionally substituted lower alkyl, cycloalkyl,cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl,optionally substituted aryl, optionally substituted heteroaryl oroptionally substituted amino or R¹⁶ and R¹⁷ taken together may formoptionally substituted 5- to 7-membered heterocyclyl with theneighboring nitrogen atom), —NR¹⁸COR¹⁹ (R¹⁸ and R¹⁹ are eachindependently hydrogen, optionally substituted lower alkyl, cycloalkyl,cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl,optionally substituted aryl, or optionally substituted heteroaryl),—NR²⁰COOR²¹ (R²⁰ is hydrogen, lower alkyl, cycloalkyl,cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl,optionally substituted aryl, or optionally substituted heteroaryl; R²¹is ester moiety), —NR²²SO₂R²³ (R²² is hydrogen, lower alkyl, cycloalkyl,cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl,optionally substituted aryl, or optionally substituted heteroaryl; R²³is lower alkyl, cycloalkyl, lower alkenyl, optionally substitutedaralkyl, optionally substituted aryl, optionally substituted heteroaryl,or lower alkylamino), —OH, lower alkoxy, —SH or lower alkylthio or R³and R⁴ taken together may form ═O, ═S, or lower alkylene dioxy; R⁵ ishydrogen, or R³ and R⁵ taken together may form a bond; R⁶ is hydrogen,—COOR²⁴ (R²⁴ is hydrogen or ester moiety), —CN, or —CH₂NR²⁵R²⁶ (R²⁵ andR²⁶ are each independently hydrogen, lower alkyl, cycloalkyl, or loweralkenyl); R⁷ is hydrogen, halogen, —CN, optionally substituted loweralkyl, cycloalkyl, cycloalkyl(lower)alkyl, optionally substituted loweralkenyl, optionally substituted aralkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted amino, —COOR³⁴(R³⁴ is hydrogen or ester moiety), —COR³⁵ (R³⁵ is hydrogen, lower alkyl,cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionallysubstituted amino, optionally substituted aryl, or optionallysubstituted heteroaryl) or —CHNOH; R⁸ is hydrogen, optionallysubstituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, loweralkenyl, optionally substituted aralkyl, optionally substituted aryl,optionally substituted heteroaryl, —COR²⁷ (R²⁷ is hydrogen, lower alkyl,cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionallysubstituted aryl, or optionally substituted heteroaryl), —COOR²⁸ (R²⁸ isester moiety), or —SO₂R²⁹ (R²⁹ is lower alkyl, cycloalkyl, optionallysubstituted lower alkenyl, optionally substituted aralkyl, optionallysubstituted aryl, optionally substituted heteroaryl), or tri-lower alkylsilyl; R⁹, R¹⁰ and R¹¹ are each independently hydrogen, halogen,optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl,optionally substituted lower alkenyl, lower alkoxy, —OH, —CN, —SR³⁰ (R³⁰is hydrogen or lower alkyl), —CONH₂, —CHO, —CHNOH, —COOR³¹ (R³¹ ishydrogen or ester moiety), —NR³²R³³ (R³² and R³³ is each independentlyhydrogen or lower alkyl), optionally substituted aryl or optionallysubstituted heteroaryl.
 2. A compound, prodrug, pharmaceuticallyacceptable salt or solvate thereof, according to claim 1, wherein R² ishydrogen
 3. A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to claim 1, wherein R³ is hydrogen.
 4. Acompound, prodrug, pharmaceutically acceptable salt or solvate thereof,according to claim 1, wherein R⁵ is hydrogen.
 5. A compound, prodrug,pharmaceutically acceptable salt or solvate thereof, according to claim1, wherein R³ and R⁵ taken together may form a bond.
 6. A compound,prodrug, pharmaceutically acceptable salt or solvate thereof, accordingto claim 1, wherein R³ and R⁴ taken together may form ═O, ═S or loweralkylenedioxy.
 7. A compound, prodrug, pharmaceutically acceptable saltor solvate thereof, according to claim 1, wherein R⁴ represents —COOR¹³(R¹³ is hydrogen or lower alkyl), —NR¹⁶R¹⁷ (R¹⁶ and R¹⁷ are eachindependently hydrogen, optionally substituted lower alkyl, cycloalkyl,lower alkenyl, optionally substituted aralkyl, optionally substitutedamino, or R¹⁶ and R¹⁷ taken together may form an optionally substituted5- to 7-membered heterocyclyl ring with the neighboring nitrogen atom),—NR¹⁸COR¹⁹ (R¹⁸ and R¹⁹ are each independently hydrogen, optionallysubstituted lower alkyl or optionally substituted aralkyl), —NR²⁰COOR²¹(R²⁰ is hydrogen, or lower alkyl; R²¹ is an ester moiety), —NR²²SO₂R²³(R²² is hydrogen; R²³ is lower alkyl or lower alkylamino), —OH, or loweralkoxy.
 8. A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to claim 1, wherein R⁴ is —COOR¹³ (R¹³ ishydrogen or methyl), —NR¹⁶R¹⁷ (R¹⁶ is hydrogen or lower alkyl, R¹⁷ ishydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkenyl,optionally substituted aralkyl, optionally substituted amino or R¹⁶ andR¹⁷ are taken together may form a optionally substituted 5- to7-membered heterocyclyl ring with the neighboring nitrogen atom),—NR¹⁸COR¹⁹ (R¹⁸ is hydrogen, R¹⁹ is hydrogen, optionally substitutedlower alkyl or optionally substituted aralkyl), —NR²⁰COOR²¹ (R²⁰ ishydrogen or methyl; R²¹ is methyl), —NR²²SO₂R²³ (R²² is hydrogen; R²³ ismethyl or methylamino), —OH, or lower alkoxy.
 9. A compound, prodrug,pharmaceutically acceptable salt or solvate thereof, described in claim1, wherein R⁴ is —NH₂, —NHCH₃ or —N(CH₃)₂.
 10. A compound, prodrug,pharmaceutically acceptable salt or solvate thereof, described in claim1, wherein R⁶ is hydrogen, COOCH₃, COOCH₂CH₃, CN, or CH₂NH₂.
 11. Acompound, prodrug, pharmaceutically acceptable salt or solvate thereof,described in claim 1, wherein R⁶ is hydrogen.
 12. A compound, prodrug,pharmaceutically acceptable salt or solvate thereof, described in claim1, wherein R⁷ is hydrogen, lower alkyl, halogen, phenyl, —COOR³⁴ (R³⁴ ismentioned before), —CHO or —CHNOH.
 13. A compound, prodrug,pharmaceutically acceptable salt or solvate thereof, described in claim1, wherein R⁷ is hydrogen, methyl, ethyl, halogen, or phenyl.
 14. Acompound, prodrug, pharmaceutically acceptable salt or solvate thereof,according to claim 1, wherein R⁸ is hydrogen, optionally substitutedlower alkyl, —COR²⁷ (R²⁷ is hydrogen, lower alkyl, cycloalkyl, loweralkenyl, optionally substituted aralkyl, optionally substituted aryl, oroptionally substituted heteroaryl), —COOR²⁸ (R²⁸ is ester moiety), or—SO₂R²⁹ (R²⁹ is lower alkyl, cycloalkyl, optionally substituted loweralkenyl, optionally substituted aralkyl, optionally substituted aryl,optionally substituted heteroaryl), or tri-lower alkyl silyl.
 15. Acompound, prodrug, pharmaceutically acceptable salt or solvate thereof,according to claim 1, wherein R⁸ is hydrogen or —SO₂R²⁹ (R²⁰ ismentioned before).
 16. A compound, prodrug, pharmaceutically acceptablesalt or solvate thereof, according to claim 1, wherein all of R⁹, R¹⁰and R¹¹ are hydrogen.
 17. A compound, prodrug, pharmaceuticallyacceptable salt or solvate thereof, according to claim 1, wherein R² ishydrogen; R³ and R⁵ are hydrogen or taken together may form a bond. 18.A compound, prodrug, pharmaceutically acceptable salt or solvatethereof, according to claim 16 and claim 17, wherein R⁶ is hydrogen,COOCH₃, COOCH₂CH₃, CN, or CH₂NH₂; R⁷ is hydrogen, lower alkyl, halogenor phenyl R⁸ is hydrogen, lower alkyl, COPh, or SO₂Ph (Ph representsphenyl).
 19. A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to claim 1, wherein R⁹ is hydrogen orhalogen.
 20. A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to claim 1, wherein R⁹ is hydrogen.
 21. Acompound, prodrug, pharmaceutically acceptable salt or solvate thereof,described in claim 1, wherein R¹⁰ is hydrogen.
 22. A compound, prodrug,pharmaceutically acceptable salt or solvate thereof, according to claim1, wherein R¹¹ is hydrogen, halogen, lower alkyl, optionally substitutedlower alkenyl, —CN, —SR³⁰ (R³⁰ is hydrogen or lower alkyl), —CONH₂,—CHO, —CHNOH, —NR³²R³³ (R³² and R³³ are each independently hydrogen orlower alkyl) or aryl.
 23. A compound, prodrug, pharmaceuticallyacceptable salt or solvate thereof, according to claim 1, wherein R¹¹ ishydrogen, halogen, methyl, —CN, or —CONH₂.
 24. A compound, prodrug,pharmaceutically acceptable salt or solvate thereof, according to claim1, wherein R¹, R², R³, R⁵, R⁶, R⁹, and R¹⁰ is hydrogen; R⁴ is —NH₂,—NHCH₃, or —N(CH₃)₂; R⁷ is hydrogen, halogen, lower alkyl, or phenyl; R⁸is hydrogen or —SO₂R²⁹ (R²⁹ is mentioned before); R¹¹ is hydrogen,halogen, lower alkyl, —CN, or —CONH₂.
 25. A pharmaceutical compositioncontaining a compound, prodrug, pharmaceutically acceptable salt orsolvate thereof according to any one of claims 1-24.
 26. A therapeuticor prophylactic medicament against the serotonin receptors mediateddiseases, comprising a compound, prodrug, pharmaceutically acceptablesalt or solvate thereof according to any one of claims 1-24.
 27. Atherapeutic or prophylactic medicament according to claim 26, whereinthe serotonine receptor is a 5-HT₆ receptor.
 28. A therapeutic orprophylactic medicament according to claim 26, wherein the disease isthat of central nervous system.
 29. A therapeutic or prophylacticmedicament according to claim 28, wherein the disease of the centralnervous system is schizophrenia, Alzheimer's disease, Parkinson'sdisease, depression, anxiety, pain, or migraine.
 30. A method fortreating or preventing the serotonin receptors mediated diseases, whichcomprises administrating to said mammals an effective amount of acompound, prodrug, pharmaceutically acceptable salt or solvate thereofaccording to any one of claims 1-24.
 31. Use of a compound, prodrug,pharmaceutically acceptable salt or solvate thereof according to any oneof claims 1-24, in order to prepare a therapeutic or prophylacticmedicament for the serotonin receptors mediated diseases.